CN104151232A - Method for preparing etocoxib - Google Patents
Method for preparing etocoxib Download PDFInfo
- Publication number
- CN104151232A CN104151232A CN201410297931.2A CN201410297931A CN104151232A CN 104151232 A CN104151232 A CN 104151232A CN 201410297931 A CN201410297931 A CN 201410297931A CN 104151232 A CN104151232 A CN 104151232A
- Authority
- CN
- China
- Prior art keywords
- compound
- sodium
- potassium
- preferred
- synthetic
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to reparation of 5-chloro-3-(4-methylsulfonyl) phenyl-2-(2-methyl-5-pyridyl) pyridine which is a high-selectivity cycloxygenase-2(COX-2) inhibitor, has the functions of preventing inflammation, clearing heat, relieving pain and the like, has a very good curative effect on signs and symptoms of osteoarthritis in the acute stage and the chronic stage and on the acute gouty arthritis, and is an important non-steride anti-inflammatory medicine. According to the method, the medicine is prepped by virtue of three steps as shown in the specification by taking 4-methylsulfonyl phenylacetic acid as a raw material.
Description
Technical field
The invention belongs to pharmaceutical chemistry field, relate to 5-chloro-3-(4-methylsulfonyl) phenyl-2-(2-methyl-5-pyridyl) pyridine preparation method.Object is to provide a kind of method of preparing simple, green, the high yield of Etoricoxib.
Background technology
Etoricoxib is a kind of highly selective cyclooxygenase-2 (COX-2) inhibitor, has anti-inflammatory, brings down a fever and the effect such as analgesia, and supervised approved by management has been clinically as NSAID (non-steroidal anti-inflammatory drug).Etoricoxib is synthetic by the development of Canadian Mike's Dan Frost company the earliest, in 2002 first in Mexico's listing, and more than 70 the country's listings such as European Union outside the Chu U.S. at present, formulation is film coating tablet, the safe and comfortable letter of trade(brand)name.
At present, for Etoricoxib, there is metastable synthesis technique.Patent EP0912518 carrys out synthesising target compound by aryl/pyridyl halogenide of palladium catalysis and the coupling of aryl/pyridyl boric acid or stannane, and this route relates to the (PPH such as Pd
3)
4, OsO
4deng the use of noble metal compound, also have the generation of a large amount of poisonous and hazardous reagent uses and waste.Methyl sulphonyl benzyl-pyridine base ketone (compound 4) and 2-chloro-1 for patent US6040319; the Etoricoxib of preparing that two (dimethylamino) the three methylene hexafluorophosphates (compound 5) of 3-carry out condensation; the more former lap tool of the method in steps simply, raw material is easy to get, can be used for the advantages such as fairly large production, is the main method of synthesizing at present Etoricoxib.In addition at patent WO9955830, WO9915503 and document Journal of Organic Chemistry (2000), 65 (25), in 8415-8420, also introduced similar approach prepared by Etoricoxib.
It is raw material that the present invention adopts 4-methylsulfonyl toluylic acid, by three-step reaction, prepares Etoricoxib, does not relate to danger and control reagent and medicine in reaction, has simple to operate.Safety, advantages of environment protection.
Summary of the invention
The invention provides the preparation method of a kind of 5-chloro-3-(4-methylsulfonyl) phenyl-2-(2-methyl-5-pyridyl) pyridine; its step is; take 4-methylsulfonyl toluylic acid and 6-methylnicotinic acid methyl esters is raw material, adopts suitable raw material and catalyzer, through three steps are synthetic, obtains.The method has simple to operate, and reaction conditions is gentle, the features such as environmental friendliness.
The reagent 1 being adopted by compound 1 synthetic compound 2 is thionyl chloride, phosphorus trichloride, phosphorus pentachloride, wherein preferred thionyl chloride.The alcohol being adopted by compound 1 synthetic compound 2 is methyl alcohol, ethanol, wherein preferred alcohol.By compound 2, react synthetic compound 4 with compound 3, the alkali that adopts 1 is tertiary butyl chlorination magnesium, sodium hydride, and sodium amide, butyllithium, preferred tertiary butylmagnesium chloride wherein, this reaction be take tetrahydrofuran (THF) as solvent.Compound 5 prepares target compound with compound 4 direct polycondensation under alkaline condition.Mol ratio between alkali 1 used and compound 2 is 1 ~ 3, and wherein preferred proportion is 2, and this temperature of reaction is chosen as 25 ~ 75 ℃, wherein preferably 45 ~ 55 ℃.Alkali 2 used is sodium hydroxide, potassium hydroxide, sodium hydride, sodium amide, sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, sodium propylate, potassium propylate, sodium butylate, butanols potassium, wherein preferred butanols potassium.
Embodiment
Further illustrate by the following examples the present invention, but not as limitation of the present invention.
embodiment:
Step 1: add 21.4 g 4-methylsulfonyl toluylic acids in 250 mL there-necked flasks, and add 110mL methylene dichloride, stirring at normal temperature, measures 29 mL thionyl chlorides (approximately 47.6 g) and slowly drip as reaction system, dropwises rear stirring reaction 1 h; Reaction solution is steamed to dry in 50 ℃ of backspins, obtain pale solid; In pale solid, add 100 mL dehydrated alcohols, stir 0.5 h, solid dissolves completely; Reaction solution is reduced to dry in 45 ℃ of backspin inspissations, obtains off-white color product, product, in 40 ℃ of dry 12 h, obtains white solid 23.9 g of compound 2, and yield is 98.76 %.
Step 2: in 250 mL there-necked flasks, add 12.1 g compounds 2 and 60 mL tetrahydrofuran (THF)s, heated and stirred, 50 ℃ of temperature controls slowly drip the tetrahydrofuran solution of 50 mL 2N tertiary butyl chlorination magnesium, reacting by heating 2 h in system; Take 7.6 g compounds 3 and be dissolved in wiring solution-forming in 40 mL tetrahydrofuran (THF)s, this solution is slowly added dropwise in above-mentioned reaction system, 50 ℃ of reaction 5 h of temperature control, TLC detection reaction terminal; Question response finishes, and to the sodium carbonate solution that drips 100 mL 1N in system, stirs 0.5 h, and reaction solution, in 50 ℃ of concentrated by rotary evaporations, is obtained to brown dirty solution; In this turbid solution, add 150 mL ethyl acetate, separatory, organic phase is washed three times with the sodium hydroxide solution of 1 N, and organic phase, with extremely dry in 45 ℃ of concentrated by rotary evaporations after anhydrous sodium sulfate drying 2 h, obtains pale solid; Gained solid is pulled an oar with normal hexane, obtain white solid 11.4 g of compound 4, yield is 78.80 %.
Step 3: in 250 mL there-necked flasks, add tetrahydrofuran solution 35 mL (butanols potassium content is about 4.1 g) of butanols potassium, 0 ℃ of temperature control, is dissolved in 10 g compounds 4 in 70 mL tetrahydrofuran (THF)s, slowly drips as reaction system; 11.0 g compounds 5 are added to reaction system, and temperature control reacts 1 h, stirs 2 h under room temperature; To the tetrahydrofuran solution that adds 30 mL acetic acid in reaction solution, add concentrated ammonia solution 25 mL after stirring 1 h, this mixture is added to 3 h that reflux, be cooled to 20 ℃, separatory, is concentrated into 20 mL by organic phase, and adds isopropyl acetate 35 mL; Produced solution is concentrated to approximately 25 mL again, and adds isopropyl acetate 130 mL, by saturated sodium bicarbonate and each washed twice of water, organic phase is concentrated into dry, obtain white solid 10.6 g of target compound 6, yield is 85.48 %.
The nuclear magnetic resonance data of compound 4 and compound 6 is as follows.
Compound 4:
1h NMR (400 MHz CDCl
3) δ 9.12 (s, 1H), 8.16 (dd, 1H,
j 1 =8.2 Hz,
j 2 =2.4 Hz), 7.90 (d, 2H,
j=8.5 Hz), 7.46 (d, 2H,
j=8.4 Hz), 7.31 (d, 1H,
j=8.2 Hz), 4.40 (s, 2H), 3.05 (s, 3H), 2.65 (s, 3H).
Compound 6:
1h NMR (400 MHz CDCl
3) δ 8.71 (d, 1H,
j=2.3 Hz), 8.39 (3,1H,
j=2.2 Hz), 7.90 (d, 2H,
j=8.4 Hz), 7.74 (d, 1H,
j=2.3Hz), 7.56 (dd, 1H,
j 1 =8.0 Hz,
j 2 =2.3 Hz), 7.40 (d, 2H,
j=8.5Hz), 7.09 (d, 1H,
j=8.0 Hz), 3.09 (s, 3H), 2.54 (s, 3H).
Claims (7)
1. prepare Etoricoxib a method, it is characterized by that to take 4-methylsulfonyl toluylic acid be raw material, adopt suitable reagent and catalyzer, through three steps are synthetic, obtain, synthetic route is:
2. according to the method for claim 1, it is characterized in that, the reagent 1 being adopted by compound 1 synthetic compound 2 is thionyl chloride, phosphorus trichloride, phosphorus pentachloride, wherein preferred thionyl chloride.
3. according to the method for claim 1, it is characterized in that, the alcohol being adopted by compound 1 synthetic compound 2 is methyl alcohol, ethanol, wherein preferred alcohol.
4. according to the method for claim 1, it is characterized in that, by compound 2, react synthetic compound 4 with compound 3, the alkali that adopts 1 is tertiary butyl chlorination magnesium, sodium hydride, and sodium amide, butyllithium, preferred tertiary butylmagnesium chloride wherein, this reaction be take tetrahydrofuran (THF) as solvent.
5. according to the method for claim 1, it is characterized in that, compound 5 prepares target compound with compound 4 direct polycondensation under alkaline condition.
6. according to claim 4 method, it is characterized in that, the mol ratio between alkali 1 used and compound 2 is 1 ~ 3, and wherein preferred proportion is 2, and this temperature of reaction is chosen as 25 ~ 75 ℃, wherein preferably 45 ~ 55 ℃.
7. according to claim 5 method, it is characterized in that, alkali 2 used is sodium hydroxide, potassium hydroxide, sodium hydride, sodium amide, sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, sodium propylate, potassium propylate, sodium butylate, butanols potassium, wherein preferred butanols potassium.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410297931.2A CN104151232A (en) | 2014-06-30 | 2014-06-30 | Method for preparing etocoxib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410297931.2A CN104151232A (en) | 2014-06-30 | 2014-06-30 | Method for preparing etocoxib |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104151232A true CN104151232A (en) | 2014-11-19 |
Family
ID=51876894
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410297931.2A Pending CN104151232A (en) | 2014-06-30 | 2014-06-30 | Method for preparing etocoxib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104151232A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113264873A (en) * | 2019-01-18 | 2021-08-17 | 华润双鹤药业股份有限公司 | Etoricoxib purification and preparation method |
| CN114989075A (en) * | 2021-12-24 | 2022-09-02 | 四川青木制药有限公司 | Preparation method of etoricoxib intermediate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040029951A1 (en) * | 2002-08-08 | 2004-02-12 | Research Institute Of Material Medica, Chinese Academy Of Medical Sciences; | Sulfonyl-containing 3,4-diaryl-3-pyrrolin-2-ones, preparation method, and medical use thereof |
| US20040058977A1 (en) * | 2002-09-16 | 2004-03-25 | Zongru Guo | Sulfonyl-containing 2,3-diarylindole compounds, methods for making same, and methods of use thereof |
| CN1809561A (en) * | 2003-02-11 | 2006-07-26 | 普罗西迪恩有限公司 | Phenylacetamides and their use as glucokinase modulators |
| WO2008012108A2 (en) * | 2006-07-28 | 2008-01-31 | Portela & Ca., S.A. | Process for the preparation of polyhydroxylated stilbenes via claisen condensation |
-
2014
- 2014-06-30 CN CN201410297931.2A patent/CN104151232A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040029951A1 (en) * | 2002-08-08 | 2004-02-12 | Research Institute Of Material Medica, Chinese Academy Of Medical Sciences; | Sulfonyl-containing 3,4-diaryl-3-pyrrolin-2-ones, preparation method, and medical use thereof |
| US20040058977A1 (en) * | 2002-09-16 | 2004-03-25 | Zongru Guo | Sulfonyl-containing 2,3-diarylindole compounds, methods for making same, and methods of use thereof |
| CN1809561A (en) * | 2003-02-11 | 2006-07-26 | 普罗西迪恩有限公司 | Phenylacetamides and their use as glucokinase modulators |
| WO2008012108A2 (en) * | 2006-07-28 | 2008-01-31 | Portela & Ca., S.A. | Process for the preparation of polyhydroxylated stilbenes via claisen condensation |
Non-Patent Citations (1)
| Title |
|---|
| IAN W.DAVIES 等: "A Practical Synthesis of a COX-2-Specific Inhibitor", 《J.ORG.CHEM.》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113264873A (en) * | 2019-01-18 | 2021-08-17 | 华润双鹤药业股份有限公司 | Etoricoxib purification and preparation method |
| CN113264873B (en) * | 2019-01-18 | 2022-11-04 | 华润双鹤药业股份有限公司 | Etoricoxib purification and preparation method |
| CN114989075A (en) * | 2021-12-24 | 2022-09-02 | 四川青木制药有限公司 | Preparation method of etoricoxib intermediate |
| CN114989075B (en) * | 2021-12-24 | 2024-05-24 | 四川青木制药有限公司 | Preparation method of etoricoxib intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104610254A (en) | Low-cost preparation method for palbociclib | |
| CN105732444B (en) | A kind of his synthetic method of Baily department | |
| CN104151232A (en) | Method for preparing etocoxib | |
| CN105732619B (en) | A kind of synthetic method of 5,6,7,8 tetrahydropyridines simultaneously [2,3 d] pyrimidines | |
| CN103833560A (en) | Preparation method of (S)-5-chloro-alpha-cyclopropinyl-2-amino-alpha-trifluoromethyl phenylcarbinol | |
| Lu et al. | A simple and convenient synthesis of 2-(perfluoroalkyl)-4H-chromenes from salicyl N-tosylimines or salicylaldehydes and methyl 2-perfluoroalkynoates | |
| CN105153149A (en) | Preparation method for selective kinases inhibitor Palbociclib | |
| CN103012241A (en) | Polysubstitution indole, synthesis method for same and synthesis application of polysubstitution indole to indomethacin | |
| Maekawa et al. | Selective introduction of a trifluoroacetyl group onto 4-vinylpyridines through magnesium-promoted reduction | |
| CN105153083A (en) | Preparation method for polysubstituted furan compound | |
| CN103896858B (en) | The preparation technology of cytosine | |
| CN108047093A (en) | A kind of preparation method of xenyl aminopropan aldehyde compound | |
| CN106699722A (en) | Synthetic method of 2,2-dichloro-1,3-benzodioxole-4-formaldehyde | |
| CN101220012B (en) | Method for synthesizing polysubstitution 4-fluorine-2(5H)-furanone | |
| CN106957237B (en) | A method of synthesis bromfenac sodium | |
| CN106632194B (en) | The method that Benzofurantone compound is prepared as CO source of release using iron pentacarbonyl | |
| CN106316892A (en) | Synthetic method of sodium houttuyfonate | |
| CN102964232A (en) | Preparation method of ketone compound and its derivatives | |
| CN103664940A (en) | Preparation method of moxifloxacin impurity | |
| CN106279236A (en) | A kind of method of synthesis 2 triisopropylsilyl acetylene Benzazole compounds | |
| CN105085190A (en) | Preparing method of 2,6-difluoro-4-bromophenol | |
| CN103980139A (en) | Naphthoic acid compound and preparation method thereof | |
| CN104926674A (en) | (Z)-3-dimethylamino-2-phenoxy-alpha, beta-unsaturated amide and preparation method thereof | |
| CN104557738A (en) | Green synthesis method of 4(3H)-quinazolinone | |
| CN103755657A (en) | Preparation method of rivaroxaban intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20141119 |
|
| WD01 | Invention patent application deemed withdrawn after publication |