CN106674142A - Preparation methods of parecoxib sodium and intermediate thereof - Google Patents
Preparation methods of parecoxib sodium and intermediate thereof Download PDFInfo
- Publication number
- CN106674142A CN106674142A CN201611116377.9A CN201611116377A CN106674142A CN 106674142 A CN106674142 A CN 106674142A CN 201611116377 A CN201611116377 A CN 201611116377A CN 106674142 A CN106674142 A CN 106674142A
- Authority
- CN
- China
- Prior art keywords
- parecoxib sodium
- preparation
- intermediate compound
- sodium intermediate
- parecoxib
- 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.)
- Pending
Links
- 229960003925 parecoxib sodium Drugs 0.000 title claims abstract description 141
- ICJGKYTXBRDUMV-UHFFFAOYSA-N trichloro(6-trichlorosilylhexyl)silane Chemical compound Cl[Si](Cl)(Cl)CCCCCC[Si](Cl)(Cl)Cl ICJGKYTXBRDUMV-UHFFFAOYSA-N 0.000 title claims abstract description 141
- 238000002360 preparation method Methods 0.000 title claims abstract description 87
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 claims abstract description 43
- 229960002004 valdecoxib Drugs 0.000 claims abstract description 42
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 238000006482 condensation reaction Methods 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 8
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 claims abstract description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract description 5
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229940092714 benzenesulfonic acid Drugs 0.000 claims abstract description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 73
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 66
- 238000003756 stirring Methods 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 238000005406 washing Methods 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 15
- 238000001291 vacuum drying Methods 0.000 claims description 12
- 238000012805 post-processing Methods 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- 150000001298 alcohols Chemical group 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- 230000001476 alcoholic effect Effects 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000004744 fabric Substances 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 6
- 239000013067 intermediate product Substances 0.000 abstract description 2
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 abstract 4
- 238000009776 industrial production Methods 0.000 abstract 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 abstract 1
- 239000002994 raw material Substances 0.000 description 16
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 14
- 238000000034 method Methods 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 9
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000010792 warming Methods 0.000 description 9
- 238000012544 monitoring process Methods 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- BXWLVQXAFBWKSR-UHFFFAOYSA-N 2-methoxy-5-methylsulfonylbenzoic acid Chemical compound COC1=CC=C(S(C)(=O)=O)C=C1C(O)=O BXWLVQXAFBWKSR-UHFFFAOYSA-N 0.000 description 3
- 230000000740 bleeding effect Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 102000004020 Oxygenases Human genes 0.000 description 1
- 108090000417 Oxygenases Proteins 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- BWHLPLXXIDYSNW-UHFFFAOYSA-N ketorolac tromethamine Chemical compound OCC(N)(CO)CO.OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 BWHLPLXXIDYSNW-UHFFFAOYSA-N 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses preparation methods of parecoxib sodium and intermediate thereof. The invention provides a preparation method of a parecoxib sodium intermediate I. The preparation method of the parecoxib sodium intermediate I comprises the following step: in the presence of a catalyst, performing condensation reaction on valdecoxib III and propionic anhydride to obtain the parecoxib sodium intermediate I, wherein the catalyst is one or more of benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid and sulfamic acid. The preparation method is simple in reaction and post-treating operation, high in yield and low in cost; the purity of the prepared intermediate product is high and can reach 99.80% or above, and the content of specific impurity valdecoxib reaches 0.02% or below and can meet the standard of an original researching manufacturer; therefore, the preparation method is suitable for industrial production. The purity of parecoxib sodium prepared from the parecoxib sodium intermediate I prepared by the preparation method provided by the invention can reach 99.80% or above and the content of the specific impurity valdecoxib reaches 0.01% or below and is higher than the standard of the original researching manufacturer.
Description
Technical field
The present invention relates to a kind of Parecoxib Sodium and its preparation method of intermediate.
Background technology
Nonsteroidal anti-inflammatory drug (NSAIDs) is widely used in treatment inflammation and slight illness, such as in arthritis and headache.This
The medicine of sample is effective, but their long-term use is subject to include the gastrointestinal side-effect of indigestion and abdominal pain and tight
The limitation of stomach or duodenum perforation and/or bleeding in the case of weight, by combine the treatment effect of tradition NSAIDs with it is very big
Improved stomach and intestine security situation, the exploitation of the suppressive drug of selective COX-2-2 revolutionizes the treatment of inflammation and pain.Ring adds
The inhibitory action of oxygenase (COX) is it is believed that at least nonsteroidal anti-inflammatory drug (NSAIDs) is played by suppressing prostaglandin synthesis
Its characteristic anti-inflammatory, the main mechanism brought down a fever with analgesic effect.The NSAIDs of in the market injection form is relatively fewer.It is parenteral to answer
Non-selective NSAIDs such as ketorolac tromethamine salt is effective antalgesic, but with the allusion quotation of the non-selective NSAIDs
Type side effect is relevant.These side effects include UGI ulcer and bleeding, especially true in gerontal patient：Renal function subtracts
Move back, this may cause fluid retention and hypertension to aggravate：And suppressing platelet function, this may make patient tend to bleeding increasing
It is many, such as during performing the operation.The side effect has seriously limited the application of non-selective NSAIDs parenteral formulations.Therefore, plus
Enter to provide the Parenteral formulations that selective COX-2-2 suppresses medicine, this will be another marked improvement in the art.
Parecoxib Sodium, English name：Parecoxib Sodium, chemical structural formula as shown in Formula II, Parecoxib Sodium
Intermediate compound I is the key intermediate for synthesizing Parecoxib Sodium.
Original according to Pharmacia ＆ Upjohn company of the U.S. grinds patent CN97193747.8 reports, Parecoxib Sodium intermediate compound I
Synthesis technique be mainly and completed by following routes.
The route is to add to dry tetrahydrochysene furan the DMAP of Parecoxib Sodium intermediate valdecoxib III and catalytic amount
Mutter in solvent, excessive propionic andydride and triethylamine is added after stirring.Room temperature reaction is concentrated to dryness after 18 hours, adds ethyl acetate
Dissolving, successively with 1N hydrochloric acid and saturated common salt water washing, organic phase anhydrous sodium sulfate drying obtains handkerchief auspicious former times after being concentrated to dryness
Cloth sodium intermediate compound I.Not only cost of material is higher for the synthetic method, and post-processing operation is relatively complicated, is not appropriate for workshop scale
Metaplasia is produced.Parecoxib Sodium intermediate valdecoxib (III) is commercial goods.
The method that another synthesis Parecoxib Sodium is reported in patent CN03806088.4, the route is by SC 69124
Sodium intermediate valdecoxib III is added to excessive propionic andydride, is added dropwise to the concentrated sulfuric acid of catalytic amount, is reacted after being heated to 80 DEG C
Until terminating, crystallization filtering after room temperature is cooled to, obtains Parecoxib Sodium intermediate compound I.In Parecoxib Sodium obtained in the method
The purity of mesosome I is relatively low, need to can just obtain purity product higher after repeated recrystallize is refined, and post-processing operation is more numerous
Trivial, yield is relatively low, is not appropriate for workshop large-scale production.
In the reference preparation of Parecoxib Sodium II Yuan Yan producers, Parecoxib Sodium intermediate valdecoxib III therein contains
It is 0.01% to measure, so the Parecoxib Sodium II of synthesis must be better than the product quality of Yuan Yan producers, in the middle of Parecoxib Sodium
Body valdecoxib III contents are reduced to less than 0.01%.It has been investigated that, the SC 69124 in Parecoxib Sodium intermediate compound I
After sodium intermediate valdecoxib III contents are less than 0.02%, the impurity III contents in Parecoxib Sodium II could be less than
0.01%.So to control the impurity III contents in Parecoxib Sodium intermediate compound I to be less than 0.02%.Each bar reported at present
Parecoxib Sodium intermediate compound I synthesis technique, can only be reduced to 0.2%, far inferior to the level of Yuan Yan producers by impurity III contents.
It is, thus, sought for a kind of effective synthetic method, reduces the content of specific impurities III and improves yield and avoid using
The specific conditions such as column chromatography, are conducive to factory to amplify production.
The content of the invention
The technical problems to be solved by the invention are to overcome the preparation side of Parecoxib Sodium intermediate in the prior art
Method impurity content is high, reaction yield is low, production cost is high, be not suitable for the defects such as industrialized production and provide a kind of handkerchief auspicious former times
The preparation method of cloth sodium and its intermediate.Preparation method of the invention reaction and post-processing operation is simple, high income, low cost,
Obtained product purity is high, be suitable for industrialized production.
The invention provides a kind of preparation method of Parecoxib Sodium intermediate compound I, it is comprised the following steps：Catalyst is present
Under conditions of, valdecoxib III and propionic andydride are carried out into condensation reaction and obtains Parecoxib Sodium intermediate compound I；Described urges
Agent is one or more in benzene sulfonic acid, p-methyl benzenesulfonic acid, methanesulfonic acid and sulfamic acid；
The preparation method of described Parecoxib Sodium intermediate compound I can be the routine side of such condensation reaction in this area
Method, particularly preferred following reaction condition in the present invention：
In the preparation method of described Parecoxib Sodium intermediate compound I, described propionic andydride and described valdecoxib III
Molar ratio preferably 3~15, further preferred 6~12, such as 9.
In the preparation method of described Parecoxib Sodium intermediate compound I, described catalyst and described valdecoxib III
Molar ratio preferably 0.01~1, further preferred 0.1~0.3, such as 0.1.
In the preparation method of described Parecoxib Sodium intermediate compound I, the temperature preferably 0~120 of described condensation reaction
DEG C, further preferred 40 DEG C~80 DEG C, such as 50 DEG C~60 DEG C.
In the preparation method of described Parecoxib Sodium intermediate compound I, the process of described condensation reaction can be using this
Routine monitoring method (such as TLC, HPLC or NMR) is monitored in field, is anti-when typically being disappeared substantially with valdecoxib III
The terminal answered, preferably 1 hour~10 hours time of described condensation reaction, further preferred 2 hours~6 hours, such as 3 is small
When or 4 hours.
In the preparation method of described Parecoxib Sodium intermediate compound I, propionic andydride can both do reaction reagent or make to react molten
Agent.
The preparation method of described Parecoxib Sodium intermediate compound I preferably uses following steps：Valdecoxib III is dissolved in
In propionic andydride, add catalyst and carry out condensation reaction and obtain Parecoxib Sodium intermediate compound I.
The preparation method of described Parecoxib Sodium intermediate compound I preferably uses following post-processing step：After reaction terminates, drop
Temperature to 0~10 DEG C, stirring, filtering, washing, dry after obtain Parecoxib Sodium intermediate compound I.Described stirring, filtering, washing and
Drying can be using the conventional method of the generic operation in this area.Preferably 1 hour~3 hours time of described stirring.It is described
Washing preferably use ether solvent；The preferred methyl tertiary butyl ether(MTBE) of described ether solvent.Described drying is preferably vacuum dried；
Preferably 50 DEG C~60 DEG C of described vacuum drying temperature；Described vacuum drying pressure preferably -0.08MPa~-0.1MPa；
Preferably 8 hours~12 hours described vacuum drying time.
The HPLC purity of Parecoxib Sodium intermediate compound I obtained in preparation method of the invention is more than 99.80%, and maximum list is miscellaneous
＜ 0.1%, raw material valdecoxib III ＜ 0.02%.
Present invention also offers the preparation method of Parecoxib Sodium II, it is comprised the following steps：It is obtained according to the method described above
After Parecoxib Sodium intermediate compound I, then in organic solvent, described Parecoxib Sodium intermediate compound I and NaOH are carried out
Salt-forming reaction, obtains Parecoxib Sodium II；
The preparation method of described Parecoxib Sodium II can be the conventional method of such salt-forming reaction in this area, this hair
Particularly preferred following reaction condition in bright：
In the preparation method of described Parecoxib Sodium II, the preferred alcohols solvent of described organic solvent；Described alcohol
Class solvent preferred alcohol.
In the preparation method of described Parecoxib Sodium II, in the middle of described organic solvent and described Parecoxib Sodium
The mass values of body I preferably 1~100, further preferred 2~20, such as 6.
In the preparation method of described Parecoxib Sodium II, described NaOH can be in the form of solid or solution
Use；When described NaOH is used as a solution, the alcohol of the preferred NaOH of solution of described NaOH
Solution；The ethanol solution of the preferred NaOH of alcoholic solution of described NaOH.
In the preparation method of described Parecoxib Sodium II, in the middle of described NaOH and described Parecoxib Sodium
The molar ratio of body I preferably 1~5, further preferred 1~2, such as 1.
In the preparation method of described Parecoxib Sodium II, preferably 50 DEG C~100 DEG C of the temperature of described salt-forming reaction,
Further preferred 60 DEG C~90 DEG C, such as 70 DEG C~80 DEG C.
The preparation method of described Parecoxib Sodium II preferably uses following steps：The alcoholic solution of NaOH is added to
In the mixture that described Parecoxib Sodium intermediate compound I is formed with organic solvent, carry out salt-forming reaction and obtain Parecoxib Sodium II
.
The preparation method of described Parecoxib Sodium II preferably uses following post-processing step：After reaction terminates, it is cooled to
30 DEG C~60 DEG C (preferably 45 DEG C~55 DEG C), stir 1 hour~3 hours (such as 1 hour)；- 5~5 DEG C are cooled to, continue to stir
The crude product of Parecoxib Sodium II is washed, be dried to obtain to 1 hour~3 hours (such as 1 hour), separation of solid and liquid.Described solid-liquid point
From preferably using centrifugation or the method for filtering.Described washing and drying can be using the routine sides of the generic operation in this area
Method, the preferred alcohols solvent of solvent that described washing is used；Described alcohols solvent preferred alcohol.The number of times of described washing is excellent
Select 1 time~3 times, such as 2 times.Described drying is preferably vacuum dried.Described dry pressure preferably -0.08MPa~-
0.1MPa.Preferably 40 DEG C~50 DEG C of described dry temperature.Preferably 6 hours~10 hours described dry time.
The crude product of Parecoxib Sodium II is preferably through the Parecoxib Sodium II being recrystallized to give after purification.Described recrystallization
The preferred alcohols solvent of solvent of use；Described alcohols solvent preferred alcohol.
The HPLC purity of Parecoxib Sodium II obtained in preparation method of the invention is more than 99.80%, single miscellaneous ＜ 0.05%,
Raw material valdecoxib III ＜ 0.01%, reach bulk drug standard.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, and obtain final product the present invention each preferably
Example.
Agents useful for same of the present invention and raw material are commercially available.
Positive effect of the invention is：Preparation method of the invention reaction and post-processing operation is simple, high income,
Low cost, obtained intermediate product purity are high (can to reach more than 99.80%, specific impurities valdecoxib content reaches
Less than 0.02%, original can be reached and grind manufacturer's standard), be suitable for industrialized production.In the middle of Parecoxib Sodium with present invention preparation
The purity of the Parecoxib Sodium that body I is prepared can reach more than 99.80%, and specific impurities valdecoxib content reaches
Less than 0.01%, reach bulk drug standard and better than the standard of Yuan Yan producers.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality
Apply among a scope.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product specification is selected.
Embodiment 1：The preparation method of Parecoxib Sodium intermediate compound I
Take raw material valdecoxib III (5.0g) to add into propionic andydride (18.6g), stirring and dissolving.Add sulfamic acid
(0.15g), is warming up to 50~60 DEG C, reacts 3 hours or so.TLC monitoring reactions are complete, are cooled to 0 DEG C or so, insulated and stirred 1
Hour or so.Filtering, is placed in vacuum drying oven, -0.08MPa~-0.1MPa after filter cake methyl tertiary butyl ether(MTBE) (10ml) drip washing,
50 DEG C are vacuum dried 8~12 hours, obtain 4.77g Parecoxib Sodium intermediate compound Is, yield 81%.HPLC purity 99.91%, it is maximum
Single miscellaneous 0.06%, raw material valdecoxib III ＜ 0.02%.
Embodiment 2：The preparation method of Parecoxib Sodium intermediate compound I
Take raw material valdecoxib III (10.0kg) to add into propionic andydride (37.2kg), stirring and dissolving.Add sulfamic acid
(0.31kg), is warming up to 50~60 DEG C, reacts 4 hours or so.TLC monitoring reactions are complete, are cooled to 0 DEG C or so, insulated and stirred 1
Hour or so.Centrifugation, is placed in vacuum drying oven, -0.08MPa~-0.1MPa after filter cake methyl tertiary butyl ether(MTBE) (20L) drip washing,
50 DEG C of dryings 8~12 hours, obtain Parecoxib Sodium intermediate (I) 9.31kg, yield 79.2%.HPLC purity 99.92%, it is maximum
Single miscellaneous 0.05%, raw material valdecoxib III ＜ 0.02%.
Embodiment 3：The preparation method of Parecoxib Sodium intermediate compound I
Take raw material valdecoxib III (5.0g) to add into propionic andydride (18.6g), stirring and dissolving.Add methanesulfonic acid
(0.15g), is warming up to 50~60 DEG C, reacts 3 hours or so.TLC monitoring reactions are complete, are cooled to 0 DEG C or so, insulated and stirred 1
Hour or so.Filtering, is placed in vacuum drying oven, -0.08MPa~-0.1MPa after filter cake methyl tertiary butyl ether(MTBE) (10ml) drip washing,
50 DEG C are vacuum dried 8~12 hours, obtain 4.80g Parecoxib Sodium intermediate compound Is, yield 81.5%.HPLC purity 99.90%, most
It is big by single miscellaneous 0.07%, raw material valdecoxib III ＜ 0.02%.
Embodiment 4：The preparation method of Parecoxib Sodium intermediate compound I
Take raw material valdecoxib III (5.0g) to add into propionic andydride (18.6g), stirring and dissolving.Add benzene sulfonic acid
(0.25g), is warming up to 50~60 DEG C, reacts 3 hours or so.TLC monitoring reactions are complete, are cooled to 0 DEG C or so, insulated and stirred 1
Hour or so.Filtering, is placed in vacuum drying oven, -0.08MPa~-0.1MPa after filter cake methyl tertiary butyl ether(MTBE) (10ml) drip washing,
50 DEG C are vacuum dried 8~12 hours, obtain 4.90g Parecoxib Sodium intermediate compound Is, yield 83.2%.HPLC purity 99.93%, most
It is big by single miscellaneous 0.05%, raw material valdecoxib III ＜ 0.02%.
Embodiment 5：The preparation method of Parecoxib Sodium intermediate compound I
Take raw material valdecoxib III (5.0g) to add into propionic andydride (18.6g), stirring and dissolving.Add p-methyl benzenesulfonic acid
(0.27g), is warming up to 50~60 DEG C, reacts 3 hours or so.TLC monitoring reactions are complete, are cooled to 0 DEG C or so, insulated and stirred 1
Hour or so.Filtering, is placed in vacuum drying oven, -0.08MPa~-0.1MPa after filter cake methyl tertiary butyl ether(MTBE) (10ml) drip washing,
50 DEG C are vacuum dried 8~12 hours, obtain 4.85g Parecoxib Sodium intermediate compound Is, yield 82.4%.HPLC purity 99.92%, most
It is big by single miscellaneous 0.05%, raw material valdecoxib III ＜ 0.02%.
Embodiment 6：The preparation method of Parecoxib Sodium II
By Parecoxib Sodium intermediate compound I (7.8Kg) to ethanol (47Kg) is added in 50L reactors, stirring is opened, add hydrogen
Oxidation sodium ethoxide solution (contain NaOH 0.85Kg), is warming up to 70~80 DEG C, and stirring 1 hour is molten clear.45~55 DEG C are cooled to,
Stirring 1 hour.- 5~5 DEG C are cooled to, continue to stir 1 hour, centrifugation is washed at twice with less than 5 DEG C of ethanol (20Kg), is taken out
Dry, vacuum drying (40~50 DEG C, -0.08~-0.1MPa) 6~10 hours obtains Parecoxib Sodium crude product 7.68Kg, handkerchief auspicious former times
Cloth sodium crude product puts into ethanol (60Kg), is warming up to 70~80 DEG C, is cooled to -5~5 DEG C, centrifugation, with the ethanol below 5 DEG C
(15Kg) is washed, and is drained, and vacuum drying (40~50 DEG C, -0.08~-0.1MPa) 6~10 hours obtains Parecoxib Sodium II
7.02Kg, yield 84.7%, HPLC purity 99.97%, maximum single miscellaneous 0.03%, raw material valdecoxib III ＜ 0.01%.
Comparative example 1：The preparation method of Parecoxib Sodium intermediate compound I is (according to the side that patent CN97193747.8 is reported
Method)
Take raw material valdecoxib III (0.5g) to add into propionic andydride (4.86g), stirring and dissolving.Add 4- dimethylaminos
Pyridine (0.083g) and triethylamine (0.17g), mixture are stirred at room temperature 18 hours.Ethyl acetate 25mL dissolvings are added, 1N is used
Hydrochloric acid solution, saturated common salt water washing, it is dried over sodium sulfate and filter.Filter vacuum concentrate, residue with ethyl acetate and oneself
Alkane is recrystallized, and obtains 0.5g Parecoxib Sodium intermediate compound Is, yield 90%.HPLC purity 97.5%, it is valdecoxib that maximum list is miscellaneous
III is 1.7%.After recrystallizing repeated recrystallize with ethyl acetate and hexane, 0.3g Parecoxib Sodium intermediate compound Is, yield are obtained
54%, HPLC purity 98.7%, it is maximum single miscellaneous for valdecoxib III is 0.6%.
Comparative example 2：The preparation method of Parecoxib Sodium intermediate compound I is (according to the side that patent CN03806088.4 is reported
Method)
Take raw material valdecoxib III (2.1g) to add to propionic andydride (8.6g), be warming up to 50~60 DEG C, add the concentrated sulfuric acid
(0.5mL).It is warming up to 80~90 DEG C to stir 1 hour, TLC monitoring reactions are complete, are cooled to 0 DEG C or so, 1 hour left side of insulated and stirred
It is right.Filtering, is placed in vacuum drying oven, -0.08MPa~-0.1MPa after filter cake methyl tertiary butyl ether(MTBE) (10ml) drip washing, and 50 DEG C true
Sky is dried 8~12 hours, obtains 1.78g Parecoxib Sodium intermediate compound Is, yield 72%.HPLC purity 94.6%, it is maximum single miscellaneous
2.3%, valdecoxib III are 0.05%.
Claims (10)
1. a kind of preparation method of Parecoxib Sodium intermediate compound I, it is characterised in that it is comprised the following steps：The bar that catalyst is present
Under part, valdecoxib III and propionic andydride are carried out into condensation reaction and obtains Parecoxib Sodium intermediate compound I；Described catalyst
It is one or more in benzene sulfonic acid, p-methyl benzenesulfonic acid, methanesulfonic acid and sulfamic acid；
2. the preparation method of Parecoxib Sodium intermediate compound I as claimed in claim 1, it is characterised in that：
In the preparation method of described Parecoxib Sodium intermediate compound I, described propionic andydride rubs with described valdecoxib III's
Your ratio is 3~15；
And/or,
In the preparation method of described Parecoxib Sodium intermediate compound I, described catalyst rubs with described valdecoxib III's
Your ratio is 0.01~1；
And/or,
In the preparation method of described Parecoxib Sodium intermediate compound I, the temperature of described condensation reaction is 0~120 DEG C；
And/or,
In the preparation method of described Parecoxib Sodium intermediate compound I, the time of described condensation reaction is 1 hour~10 small
When.
3. the preparation method of Parecoxib Sodium intermediate compound I as claimed in claim 2, it is characterised in that：
In the preparation method of described Parecoxib Sodium intermediate compound I, described propionic andydride rubs with described valdecoxib III's
Your ratio is 6~12；
And/or,
In the preparation method of described Parecoxib Sodium intermediate compound I, described catalyst rubs with described valdecoxib III's
Your ratio is 0.1~0.3；
And/or,
In the preparation method of described Parecoxib Sodium intermediate compound I, the temperature of described condensation reaction is 40 DEG C~80 DEG C；
And/or,
In the preparation method of described Parecoxib Sodium intermediate compound I, the time of described condensation reaction is 2 hours~6 hours.
4. the preparation method of Parecoxib Sodium intermediate compound I as claimed in claim 3, it is characterised in that：
In the preparation method of described Parecoxib Sodium intermediate compound I, described propionic andydride rubs with described valdecoxib III's
Your ratio is 9；
And/or,
In the preparation method of described Parecoxib Sodium intermediate compound I, described catalyst rubs with described valdecoxib III's
Your ratio is 0.1；
And/or,
In the preparation method of described Parecoxib Sodium intermediate compound I, the temperature of described condensation reaction is 50 DEG C~60 DEG C；
And/or,
In the preparation method of described Parecoxib Sodium intermediate compound I, the time of described condensation reaction is 3 hours or 4 hours.
5. the preparation method of Parecoxib Sodium intermediate compound I as claimed in claim 1, it is characterised in that：
The preparation method of described Parecoxib Sodium intermediate compound I uses following steps：Valdecoxib III is dissolved in propionic andydride
In, add catalyst and carry out condensation reaction and obtain Parecoxib Sodium intermediate compound I；
And/or,
The preparation method of described Parecoxib Sodium intermediate compound I uses following post-processing step：After reaction terminates, 0 is cooled to~
10 DEG C, Parecoxib Sodium intermediate compound I is obtained after stirring, filtering, washing, drying.
6. the preparation method of Parecoxib Sodium intermediate compound I as claimed in claim 5, it is characterised in that：
In the post-processing step that the preparation method of described Parecoxib Sodium intermediate compound I is used, the time of described stirring is 1 small
When~3 hours；
And/or,
In the post-processing step that the preparation method of described Parecoxib Sodium intermediate compound I is used, described washing is molten using ethers
Agent；
And/or,
In the post-processing step that the preparation method of described Parecoxib Sodium intermediate compound I is used, described drying is vacuum drying.
7. a kind of preparation method of Parecoxib Sodium II, it is characterised in that it is comprised the following steps：According to claim 1~6 times
Preparation method described in one is obtained after Parecoxib Sodium intermediate compound I, then in organic solvent, by described Parecoxib Sodium
Intermediate compound I carries out salt-forming reaction with NaOH, obtains Parecoxib Sodium II；
8. the preparation method of Parecoxib Sodium II as claimed in claim 7, it is characterised in that：
In the preparation method of described Parecoxib Sodium II, described organic solvent is alcohols solvent；
And/or,
In the preparation method of described Parecoxib Sodium II, described organic solvent and described Parecoxib Sodium intermediate compound I
Mass values be 1~100；
And/or,
In the preparation method of described Parecoxib Sodium II, described NaOH is used in the form of solid or solution；
And/or,
In the preparation method of described Parecoxib Sodium II, described NaOH and described Parecoxib Sodium intermediate compound I
Molar ratio be 1~5；
And/or,
In the preparation method of described Parecoxib Sodium II, the temperature of described salt-forming reaction is 50 DEG C~100 DEG C；
The preparation method of described Parecoxib Sodium II uses following steps：The alcoholic solution of NaOH is added to described handkerchief
In the mixture that auspicious former times cloth sodium intermediate compound I is formed with organic solvent, carry out salt-forming reaction and obtain Parecoxib Sodium II；
And/or,
The preparation method of described Parecoxib Sodium II uses following post-processing step：After reaction terminates, 30 DEG C~60 are cooled to
DEG C, stir 1 hour~3 hours；- 5~5 DEG C are cooled to, continue to stir 1 hour~3 hours, separation of solid and liquid is washed, is dried to obtain
The crude product of Parecoxib Sodium II.
9. the preparation method of Parecoxib Sodium II as claimed in claim 8, it is characterised in that：
In the preparation method of described Parecoxib Sodium II, described alcohols solvent is ethanol；
And/or,
In the preparation method of described Parecoxib Sodium II, described organic solvent and described Parecoxib Sodium intermediate compound I
Mass values be 2~20；
And/or,
It is described when described NaOH is used as a solution in the preparation method of described Parecoxib Sodium II
NaOH solution for NaOH alcoholic solution；
And/or,
In the preparation method of described Parecoxib Sodium II, described NaOH and described Parecoxib Sodium intermediate compound I
Molar ratio be 1~2；
And/or,
In the preparation method of described Parecoxib Sodium II, the temperature of described salt-forming reaction is 60 DEG C~90 DEG C；
And/or,
The crude product of Parecoxib Sodium II is by being recrystallized to give Parecoxib Sodium II after purification.
10. the preparation method of Parecoxib Sodium II as claimed in claim 9, it is characterised in that：
In the preparation method of described Parecoxib Sodium II, described organic solvent and described Parecoxib Sodium intermediate compound I
Mass values be 6；
And/or,
In the preparation method of described Parecoxib Sodium II, when described NaOH in the form of alcoholic solution when to use, institute
The alcoholic solution of the NaOH stated is the ethanol solution of NaOH；
And/or,
In the preparation method of described Parecoxib Sodium II, described NaOH and described Parecoxib Sodium intermediate compound I
Molar ratio be 1；
And/or,
In the preparation method of described Parecoxib Sodium II, the temperature of described salt-forming reaction is 70 DEG C~80 DEG C；
And/or,
The solvent that described recrystallization is used is alcohols solvent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611116377.9A CN106674142A (en) | 2016-12-07 | 2016-12-07 | Preparation methods of parecoxib sodium and intermediate thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611116377.9A CN106674142A (en) | 2016-12-07 | 2016-12-07 | Preparation methods of parecoxib sodium and intermediate thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106674142A true CN106674142A (en) | 2017-05-17 |
Family
ID=58868373
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611116377.9A Pending CN106674142A (en) | 2016-12-07 | 2016-12-07 | Preparation methods of parecoxib sodium and intermediate thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106674142A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110240570A (en) * | 2018-03-07 | 2019-09-17 | 浙江震元制药有限公司 | A kind of preparation method of SC 69124 sodium impurity |
| CN112028850A (en) * | 2019-06-03 | 2020-12-04 | 鲁南制药集团股份有限公司 | Intermediate compound of parecoxib sodium |
| CN112028851A (en) * | 2019-06-03 | 2020-12-04 | 鲁南制药集团股份有限公司 | Parecoxib sodium intermediate compound |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1336602A1 (en) * | 2002-02-13 | 2003-08-20 | Giovanni Scaramuzzino | Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases |
| CN104250232A (en) * | 2013-06-26 | 2014-12-31 | 四川唯拓生物医药有限公司 | Preparation method of parecoxib sodium |
-
2016
- 2016-12-07 CN CN201611116377.9A patent/CN106674142A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1336602A1 (en) * | 2002-02-13 | 2003-08-20 | Giovanni Scaramuzzino | Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases |
| CN104250232A (en) * | 2013-06-26 | 2014-12-31 | 四川唯拓生物医药有限公司 | Preparation method of parecoxib sodium |
Non-Patent Citations (2)
| Title |
|---|
| JOHN J. TALLEY等: "N-[[(5-Methyl-3-phenylisoxazol-4-yl)-phenyl]sulfonyl]propanamide, Sodium Salt, Parecoxib Sodium: A Potent and Selective Inhibitor of COX-2 for Parenteral Administration", 《J. MED. CHEM.》 * |
| 王凯等: "帕瑞昔布的合成", 《中国医药工业杂志》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110240570A (en) * | 2018-03-07 | 2019-09-17 | 浙江震元制药有限公司 | A kind of preparation method of SC 69124 sodium impurity |
| CN112028850A (en) * | 2019-06-03 | 2020-12-04 | 鲁南制药集团股份有限公司 | Intermediate compound of parecoxib sodium |
| CN112028851A (en) * | 2019-06-03 | 2020-12-04 | 鲁南制药集团股份有限公司 | Parecoxib sodium intermediate compound |
| CN112028851B (en) * | 2019-06-03 | 2023-05-02 | 鲁南制药集团股份有限公司 | Parecoxib sodium intermediate compound |
| CN112028850B (en) * | 2019-06-03 | 2023-05-02 | 鲁南制药集团股份有限公司 | Intermediate compound of parecoxib sodium |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104250232A (en) | Preparation method of parecoxib sodium | |
| CN111646922B (en) | Synthetic method of 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid | |
| CN106674142A (en) | Preparation methods of parecoxib sodium and intermediate thereof | |
| CN110590635A (en) | Preparation method of levetiracetam and intermediate thereof | |
| CN106256824A (en) | A kind of preparation method of high-purity De Lasha star meglumine salt | |
| CN108285438B (en) | Synthesis process of benzyl ribose lactone | |
| CN106188040A (en) | A kind of Fevipiprant and the preparation method of intermediate thereof | |
| CN103864802A (en) | Preparation method of high-purity asenapine maleate | |
| TW202200546A (en) | Preparation method of aromatic ether compound | |
| CN105001098B (en) | A kind of preparation method of 3 (R)/(S)-amino-n-butyl alcohol | |
| CN114105872B (en) | Intermediate for preparing procaterol hydrochloride and preparation method thereof | |
| CN111116587A (en) | Preparation method of avibactam intermediate compound | |
| CN114195712B (en) | Intermediate capable of being used for preparing procaterol hydrochloride and preparation method thereof | |
| CN112939814B (en) | Preparation method of deuterated dacarbazine intermediate | |
| CN110551052A (en) | Preparation method of (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate | |
| CN101838243B (en) | Method for refining telmisartan | |
| CN111004141B (en) | New method for synthesizing nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide | |
| CN104557678A (en) | Method for preparing aranidipine | |
| CN113045583B (en) | Preparation method of pinoxaden metabolite | |
| CN106542958A (en) | A kind of preparation method of adjacent Iodoaniline | |
| CN107382898B (en) | Energetic material based on ANPZ energetic parent structure and synthetic method thereof | |
| CN100391946C (en) | Method for preparing amlodipine benzenesulfonate | |
| FR3011839A1 (en) | PROCESS FOR THE PREPARATION OF ACETAMIDOPHENYL DERIVATIVES | |
| CN111019016B (en) | Synthesis method of sugammadex impurity | |
| Jacobs et al. | ON NITRO-AND AMINOPHENOXYACETIC ACIDS. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170517 |