CN104788362A - Preparation method of etoricoxib or pharmaceutically acceptable salts thereof - Google Patents
Preparation method of etoricoxib or pharmaceutically acceptable salts thereof Download PDFInfo
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- CN104788362A CN104788362A CN201410025214.4A CN201410025214A CN104788362A CN 104788362 A CN104788362 A CN 104788362A CN 201410025214 A CN201410025214 A CN 201410025214A CN 104788362 A CN104788362 A CN 104788362A
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- etoricoxib
- chloropyridine
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- 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
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Abstract
The invention discloses a preparation method of etoricoxib. The method comprises the following steps: 1, reacting 2-chloromalonaldehyde (compound 1) with p-methylthiophenyl acetamide (compound 2) to prepare 2-hydroxy-3-p-methylthiophenyl-5-chloropyridine (compound 3); 2, reacting the compound 3 with phosphorus oxyhalide to prepare 2-halo-3-p-methylthiophenyl-5-chloropyridine (compound 4); 3, reacting the compound 4 with hydrogen peroxide to prepare 2-halo-3-p-methylsulfonyl-5-chloropyridine (compound 5); and 4, coupling the compound 5 with 2-methyl-pyridine-5-boric acid under the catalysis of palladium to obtain etoricoxib. The preparation method has the advantages of high purity, high yield, low cost and simple operation.
Description
Technical field
The present invention relates to the preparation method of a kind of antiphlogiston Etoricoxib or its pharmacy acceptable salt.
Background technology
Etoricoxib (Etoricoxib), chemical name be the chloro-2-of 5-(2-methyl-5-pyridyl)-3-to methanesulfonylphenYl pyridine, be the effective as selective inhibitor of cyclooxygenase-2, it has anti-inflammatory, brings down a fever and analgesic properties.Etoricoxib supervised approved by management is used as NSAID (non-steroidal anti-inflammatory drug) clinically.This medicine goes on the market as film-coated tablet, and commodity are called Arcoxia, and its structural formula is as follows:
This compound is originally presented in EP0912518B1, and its preparation method is synthesized by the aryl/pyridyl halogenide of palladium chtalyst and the coupling of aryl/pyridinylboronic acid or stannane, and above-mentioned preparation method is difficult to scale operation and Material Cost is expensive.
EP0975596B1 describes the method for the preparation of this compound, wherein forms pyridine moiety by the condensation of 2-chlorine third two-aldehyde and methyl sulphonyl benzyl-pyridine base ketone with appropriate yield.
EP1023266B1 discloses the method being prepared described compound by the condensation of the dibasic propenal of 2,3-and methyl sulphonyl benzyl-pyridine base ketone with appropriate yield.EP1023266B1 also illustrates the method for the preparation of midbody compound methyl sulphonyl benzyl-pyridine base ketone; the method is by reacting the Weinreb acid amides of halogenation methylthiobenzyl magnesium and pyridine moiety to form methylthiobenzyl pyridyl ketone; then the oxidation of thioether is carried out, to provide methyl sulphonyl benzyl-pyridine base ketone.
EP1071745B1 (also see US 6,040,319; WO 99/55830) describe method for the preparation of described compound; the method is under the reaction conditions of alkalescence; make methyl sulphonyl benzyl-pyridine base ketone and 2-chloro-1; 3-two (dimethylamino) three methylene hexafluorophosphate (2-chloro-1,3-bis (dimethylamino) trimethinium hexafluorophosphate) carries out condensation reaction.Reported for the synthesis of the chloro-3-of 5-(4-methylthio group phenyl)-6 '-methyl-[2; 3 '] dipyridyl and the chloro-3-of 5-(4-methanesulphonylphenyl)-6 '-methyl-[2; 3 '] similar approach (Org.Lett. (2000) of dipyridyl; 2 (15); 2339-2341); wherein 2-chloro-1,3-two (dimethylamino) three methylene hexafluorophosphate and methylthiobenzyl pyridyl ketone or methyl sulphonyl benzyl-pyridine base ketone react under the reaction conditions of alkalescence.
The synthesis of 2-chlorine mda is reported (Ber.Deut.Chem.Ges. (1904) 37,4638) 1904 by Diekmann back.The synthesis of 2-chlorine mda and be applied to 1975 and summarized widely (Angew.Chem.Int.Ed (1975) 14,86) by Rechardt and Halbritter.Because easily can obtain with not expensive economically, 2-chlorine mda is suitable for the synthesis of described compound.
The preparation being described in the Propenal derivative of EP1023266B1 needs the additional synthesis step prepared after 2-chlorine mda, and this increases generation cost and environmental risk.
The 2-reported in EP1071745B1 chloro-1, the preparation of 3-two (dimethylamino) three methylene hexafluorophosphate relates to the chemical substance such as phosphoryl chloride using danger, it also can cause the chemical substance harmful to Occupational health, dangerous chemical substance such as DMF.Relate to the risk in the method increase method control of the chemical substance of these danger and cause the possible risk to operator and environment.
Summary of the invention
For deficiency of the prior art, the invention provides the preparation method of a kind of new Etoricoxib or its pharmacy acceptable salt, the method is simple to operate, and yield is higher, and products obtained therefrom purity is high, and quality is good.
Technical solution of the present invention is as follows:
A compound 1 is prepared 2-hydroxyl-3-to methylthio group phenyl-5-chloropyridine (compound 2) with reacting methylthio phenyl ethanamide by (), compound 1 structure is as follows:
, substituent X
1be selected from OH, halogen and OR, described R is alkyl-carbonyl, aryl carbonyl, alkyl sulphonyl or aryl sulfonyl, preferred OH, Cl or Br, is 1:1-2 to the mol ratio of methylthio phenyl ethanamide and compound 1, preferred 1:1-1.5;
B compound 2 and three oxyhalogen phosphorus reactions are prepared 2-halo-3-to methylthio group phenyl-5-chloropyridine (compound 3) by (), described three oxyhalogen phosphorus are selected from phosphorus oxychloride or tribromo oxygen phosphorus;
C compound 3 is carried out oxidizing reaction and prepares 2-halo-3-to methanesulfonylphenYl-5-chloropyridine (compound 4) by (), described oxidizing reaction adopts hydrogen peroxide or Peracetic Acid as oxygenant, optionally, add oxide catalyst in described oxidizing reaction, described oxide catalyst is selected from Sodium orthomolybdate, sodium wolframate, ammonium molybdate, ammonium tungstate, potassium molybdate and potassium wolframate;
D compound 4 and the coupling under palladium chtalyst of 2-methvl-pyridinium-5-boric acid are obtained Etoricoxib by (), described palladium catalyst is selected from Pd (PPh
3)
4, Pd (OAc)
2or PdCl
2;
E Etoricoxib and acid-respons optionally, are prepared its pharmacy acceptable salt by (), described acid comprises: hydrochloric acid, nitric acid, sulfuric acid, methylsulfonic acid, tosic acid, acetic acid, phosphoric acid etc.
Embodiment
Embodiment 1
2-hydroxyl-3-is to the preparation of methylthio group phenyl-5-chloropyridine (compound 2)
By 2-chlorine mda (16.0g, about 0.15mol) and to methylthio phenyl ethanamide (18.1g, about 0.1mol) be added to ethanol (150ml), stirred at ambient temperature 10min, slow dropping 3ml pyridine, be warming up to backflow gradually, stirring reaction 4 hours, reaction terminates rear steaming and desolventizes, with saturated solution of sodium bicarbonate (3 × 50ml) and salt water washing after product acetic acid ethyl dissolution, with concentrated after anhydrous sodium sulfate drying, obtain resistates crystallization in hexane/ether, obtain 2-hydroxyl-3-to methylthio group phenyl-5-chloropyridine 24.3g.
Embodiment 2a
By 2-hydroxyl-3-to methylthio group phenyl-5-chloropyridine (15.1g, about 0.06mol) in sealed can with POCl
3(150ml) together 140 DEG C of heating 15 hours, after being cooled to room temperature, unnecessary POCl is removed under reduced pressure
3. residue with ethyl acetate and water dilution, be then neutralized to PH with saturated sodium bicarbonate solution and be about 7.Take out organic phase, also concentrated with salt water washing, residual solid is recrystallization in hexane/ether, obtains the chloro-3-of 2,5-bis-to methylthio phenyl yl pyridines 13.8g.
Embodiment 2b
By the POCl in embodiment 2a
3replace with POBr
3, remaining reaction condition remains unchanged, and obtains the bromo-3-of 2-to methylthio group phenyl-5-chloropyridine 16.5g.
Embodiment 3a
Sodium orthomolybdate (1.2g, 0.004mol) is added to the chloro-3-of 2,5-bis-to methylthio phenyl yl pyridines (27.0g, about 0.1mol) and sulfuric acid (4.9g, the about 0.05mol) solution in methyl alcohol (250ml).Solution is heated to 55 DEG C, adds the hydrogen peroxide of 40ml30%.Reaction mixture is kept stirring 15min, adds the NaHSO of 60ml30%
3.Then reaction mixture is cooled to room temperature, under reduced pressure removes organic solvent, add 100ml water.By ethyl acetate washing (2 × 50ml).By solution with 30% NaOH solution be neutralized to PH and be about 7, collecting precipitation, wash with water.Solid aqueous ethanol solution weight crystallization, vacuum-drying obtains the chloro-3-of 2,5-bis-to methanesulfonylphenYl pyridine 29.4g.
Embodiment 3b
Chloro-in embodiment 3a 2,5-bis-3-is replaced with the bromo-3-of 2-to methylthio group phenyl-5-chloropyridine to methylthio phenyl yl pyridines, and remaining reaction condition remains unchanged, and obtains the bromo-3-of 2-to methanesulfonylphenYl-5-chloropyridine 29.0g.
Embodiment 4a
By chloro-for 2,5-bis-3-to methanesulfonylphenYl pyridine (30.2g, about 0.1mol), 2-methvl-pyridinium-3-boric acid (13.7g, about 0.1mol), 120ml aqueous sodium carbonate (2M) and 1.2g Pd (PPh
3)
4at ethanol/toluene (240ml; mixture reflux 1:1) 15 hours; mixture is cooled to room temperature, through diatomite filtration, filtrate water and salt water washing (2 × 100ml); with concentrated after anhydrous sodium sulfate drying; obtain resistates crystallization in hexane/ether, obtain the chloro-2-of 5-(2-methyl-5-pyridyl)-3-to methanesulfonylphenYl pyridine, i.e. Etoricoxib 33.4g; product is analyzed through HPLC, and purity is 97.3%.
Embodiment 4b
By 2 in embodiment 4a; the chloro-3-of 5-bis-replaces with the bromo-3-of 2-to methanesulfonylphenYl-5-chloropyridine to methanesulfonylphenYl pyridine; remaining reaction condition remains unchanged; obtain the chloro-2-of 5-(2-methyl-5-pyridyl)-3-to methanesulfonylphenYl pyridine; namely Etoricoxib 35.2g product is analyzed through HPLC, and purity is 98.0%.
Claims (7)
1. a preparation method for Etoricoxib or its pharmacy acceptable salt, is characterized in that comprising the following steps:
A compound 1 is prepared 2-hydroxyl-3-to methylthio group phenyl-5-chloropyridine with reacting methylthio phenyl ethanamide by (), compound 1 structure is as follows:
, X
1be selected from OH, halogen and OR, described R is alkyl-carbonyl, aryl carbonyl, alkyl sulphonyl or aryl sulfonyl;
B step (a) product and three oxyhalogen phosphorus reactions are prepared 2-halo-3-to methylthio group phenyl-5-chloropyridine by (); C step (b) product is carried out oxidizing reaction and prepares 2-halo-3-to methanesulfonylphenYl-5-chloropyridine by ();
D () coupling under palladium chtalyst obtains Etoricoxib by step (c) product and 2-methvl-pyridinium-5-boric acid;
E Etoricoxib and acid-respons optionally, are prepared its pharmacy acceptable salt by ().
2. preparation method according to claim 1, is characterized in that: substituent X in described step (a)
1preferred OH, Cl or Br.
3. preparation method according to claim 1 and 2, is characterized in that: in described step (b), three oxyhalogen phosphorus are selected from phosphorus oxychloride or tribromo oxygen phosphorus.
4. preparation method according to claim 1 and 2, is characterized in that: the oxidizing reaction of described step (c) adopts hydrogen peroxide or Peracetic Acid as oxygenant.
5. preparation method according to claim 4, is characterized in that: add oxide catalyst in the oxidizing reaction of described step (c), and described oxide catalyst is selected from Sodium orthomolybdate, sodium wolframate, ammonium molybdate, ammonium tungstate, potassium molybdate and potassium wolframate.
6. preparation method according to claim 1 and 2, is characterized in that: the palladium catalyst in described step (d) is selected from Pd (PPh
3)
4, Pd (OAc)
2or PdCl
2.
7. preparation method according to claim 1 and 2, is characterized in that: be 1:1-2 to the mol ratio of methylthio phenyl ethanamide and compound 1, preferred 1:1-1.5.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104761489A (en) * | 2014-06-23 | 2015-07-08 | 济南三元化工有限公司 | Method for preparing etoricoxib and pharmaceutically acceptable salt thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1225085A (en) * | 1996-07-18 | 1999-08-04 | 麦克弗罗斯特(加拿大)有限公司 | Substituted pyridines as selective cyclooxygenase-2 inhibitors |
| CN1774422A (en) * | 2003-02-13 | 2006-05-17 | 阿尔米雷尔普罗迪斯制药有限公司 | 2,3'-bipyridines derivatives as selective cox-2 inhibitors |
| CN103204803A (en) * | 2012-01-13 | 2013-07-17 | 阿尔弗雷德·E·蒂芬巴赫尔有限责任两合公司 | Method used for synthesizing etoricoxib |
-
2014
- 2014-01-21 CN CN201410025214.4A patent/CN104788362A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1225085A (en) * | 1996-07-18 | 1999-08-04 | 麦克弗罗斯特(加拿大)有限公司 | Substituted pyridines as selective cyclooxygenase-2 inhibitors |
| CN1774422A (en) * | 2003-02-13 | 2006-05-17 | 阿尔米雷尔普罗迪斯制药有限公司 | 2,3'-bipyridines derivatives as selective cox-2 inhibitors |
| CN103204803A (en) * | 2012-01-13 | 2013-07-17 | 阿尔弗雷德·E·蒂芬巴赫尔有限责任两合公司 | Method used for synthesizing etoricoxib |
Non-Patent Citations (2)
| Title |
|---|
| 3-溴-1,6-萘啶-5(6H)-酮的合成: "3-溴-1,6-萘啶-5(6H)-酮的合成", 《华中师范大学学报（自然科学版）》 * |
| RICHARD W. FRIESEN ET AL.,: "2-PYRIDINYL-3-(4-METHYLSULFONYL)PHENYLPYRIDINES: SELECTIVE AND ORALLY ACTIVE CYCLOOXYGENASE-2 INHIBITORS", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104761489A (en) * | 2014-06-23 | 2015-07-08 | 济南三元化工有限公司 | Method for preparing etoricoxib and pharmaceutically acceptable salt thereof |
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Application publication date: 20150722 |