ITMI20121947A1 - PROCESS OF SYNTHESIS OF AN INTERMEDIATE IN THE PRODUCTION OF ETORICOXIB - Google Patents
PROCESS OF SYNTHESIS OF AN INTERMEDIATE IN THE PRODUCTION OF ETORICOXIB Download PDFInfo
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- ITMI20121947A1 ITMI20121947A1 IT001947A ITMI20121947A ITMI20121947A1 IT MI20121947 A1 ITMI20121947 A1 IT MI20121947A1 IT 001947 A IT001947 A IT 001947A IT MI20121947 A ITMI20121947 A IT MI20121947A IT MI20121947 A1 ITMI20121947 A1 IT MI20121947A1
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- reaction
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- methylpyridin
- acid
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- 238000000034 method Methods 0.000 title claims description 32
- 230000015572 biosynthetic process Effects 0.000 title claims description 12
- 238000003786 synthesis reaction Methods 0.000 title claims description 12
- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 title description 10
- 229960004945 etoricoxib Drugs 0.000 title description 10
- 238000004519 manufacturing process Methods 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims description 22
- -1 6-methylpyridin-3-yl Chemical group 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 16
- WFIFHOWQEJADPH-UHFFFAOYSA-N 2-chloro-4-(2-oxo-4-phenylpyrrolidin-1-yl)benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC=C1N1C(=O)CC(C=2C=CC=CC=2)C1 WFIFHOWQEJADPH-UHFFFAOYSA-N 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 10
- 238000007254 oxidation reaction Methods 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- BBPATOFBGJZMJM-UHFFFAOYSA-N 2-(4-methylsulfanylphenyl)acetonitrile Chemical compound CSC1=CC=C(CC#N)C=C1 BBPATOFBGJZMJM-UHFFFAOYSA-N 0.000 claims description 7
- OBCGEALAAFPYBA-UHFFFAOYSA-N 3-(6-methylpyridin-3-yl)-2-(4-methylsulfanylphenyl)-3-oxopropanenitrile Chemical compound C1=CC(SC)=CC=C1C(C#N)C(=O)C1=CC=C(C)N=C1 OBCGEALAAFPYBA-UHFFFAOYSA-N 0.000 claims description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 7
- 238000006114 decarboxylation reaction Methods 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 230000003647 oxidation Effects 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- 239000012153 distilled water Substances 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 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 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 3
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical group [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 150000004703 alkoxides Chemical class 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 238000001816 cooling Methods 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 239000000543 intermediate Substances 0.000 description 11
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 3
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 3
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 1
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940124347 antiarthritic drug Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000002825 nitriles Chemical group 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/57—Nitriles
Description
“PROCESSO DI SINTESI DI UN INTERMEDIO NELLA PRODUZIONE DI ETORICOXIB†⠀ œPROCESS OF SYNTHESIS OF AN INTERMEDIATE IN THE PRODUCTION OF ETHORICOXIBâ €
Campo del invenzione Field of the invention
La presente invenzione riguarda un processo di sintesi di 1-(6-metilpiridin-3-il)-2-[(4-metilsulfonil)fenil]etanone, un intermedio chiave nella produzione di Etoricoxib. The present invention relates to a synthesis process of 1- (6-methylpyridin-3-yl) -2 - [(4-methylsulfonyl) phenyl] ethanone, a key intermediate in the production of Etoricoxib.
Stato della Tecnica State of the art
Etoricoxib à ̈ il composto avente nome IUPAC 5-cloro-6’-metil-3-[4-(metilsulfonil)fenil]-2,3’-bipiridina; questo composto à ̈ un inibitore selettivo della COX-2 (circa 100 volte più selettivo nei confronti di COX-2 che di COX-1), e viene impiegato nella formulazione di farmaci antinfiammatori, analgesici e antiartritici con ridotti effetti collaterali a livello gastrico. Etoricoxib is the compound with the IUPAC name 5-chloro-6â € ™ -methyl-3- [4- (methylsulfonyl) phenyl] -2.3â € ™ -bipyridine; this compound is a selective inhibitor of COX-2 (about 100 times more selective towards COX-2 than COX-1), and is used in the formulation of anti-inflammatory, analgesic and anti-arthritic drugs with reduced gastric side effects.
Il gruppo di composti di cui fa parte Etoricoxib à ̈ stato descritto per la prima volta nella domanda di brevetto internazionale WO 98/03484 A1, che riporta anche alcuni possibili schemi di sintesi di questi composti. Altre vie di sintesi di Etoricoxib sono descritte nelle domande di brevetto WO 98/47871 A1 e WO 99/55830 A2, e ne 'articolo "A practical synthesis of a COX-2-specific inhibitor†, I.W. Davies et al., J Org Chem. 65(25), pagg. 8415-8420. The group of compounds to which Etoricoxib belongs was described for the first time in the international patent application WO 98/03484 A1, which also reports some possible synthesis schemes of these compounds. Other ways of synthesis of Etoricoxib are described in patent applications WO 98/47871 A1 and WO 99/55830 A2, and in the article "A practical synthesis of a COX-2-specific inhibitorâ €, I.W. Davies et al., J Org Chem. 65 (25), pp. 8415-8420.
Un’ulteriore via di sintesi di Etoricoxib, migliorata rispetto a quelle descritte nei documenti precedenti, à ̈ riportata nella domanda di brevetto WO 2012/066570 A2. In questa via di sintesi, i composti 6-metilnicotinato di metile e 4-(metiltio)benzilcianuro vengono fatti reagire a dare 3-(6-metilpiridin-3-il)-2-(4-metilsulfanilfenil)-3-ossoproprionitrile (composto C sotto riportato), secondo lo schema: A further way of synthesis of Etoricoxib, improved with respect to those described in the previous documents, is reported in the patent application WO 2012/066570 A2. In this synthesis route, the methyl 6-methylnicotinate and 4- (methylthio) benzylcyanide compounds are reacted to give 3- (6-methylpyridin-3-yl) -2- (4-methylsulfanylphenyl) -3-oxoproprionitrile (compound C below), according to the scheme:
A B C A B C
Il gruppo cianuro del composto C viene poi idrolizzato al corrispondente acido carbossilico, e successivamente sottoposto a decarbossilazione termica a dare il composto 1 -(6-metil-3-piridinil)-2-ciano-[(4-metiltio)fenil]etanone, D: The cyanide group of compound C is then hydrolyzed to the corresponding carboxylic acid, and subsequently subjected to thermal decarboxylation to give compound 1 - (6-methyl-3-pyridinyl) -2-cyano - [(4-methylthio) phenyl] ethanone, D:
Il composto D viene successivamente ossidato a fornire l’intermedio di produzione di Etoricoxib 1-(6-metilpiridin-3-il)-2-[(4-metilsulfonil)fenil]etanone, (I): Compound D is subsequently oxidized to provide the Etoricoxib production intermediate 1- (6-methylpyridin-3-yl) -2 - [(4-methylsulfonyl) phenyl] ethanone, (I):
che può poi essere trasformato in Etoricoxib con successivi passaggi di processo. La sintesi del composto (I) secondo il processo di WO 2012/066570 A2 à ̈ riportata nell’esempio 29 dello stesso documento, e dimostra che il composto (I) viene ottenuto con una purezza HPLC del 92,5%. which can then be transformed into Etoricoxib with subsequent process steps. The synthesis of compound (I) according to the process of WO 2012/066570 A2 is reported in example 29 of the same document, and shows that compound (I) is obtained with an HPLC purity of 92.5%.
Sommario dell’invenzione Summary of the invention
Scopo della presente invenzione à ̈ quello di fornire un processo migliorato per la sintesi di 1-(6-metilpiridin-3-il)-2-[(4-metilsulfonil)fenil]etanone. The purpose of the present invention is to provide an improved process for the synthesis of 1- (6-methylpyridin-3-yl) -2 - [(4-methylsulfonyl) phenyl] ethanone.
Questo ed altri scopi vengono ottenuti con la presente invenzione, che à ̈ relativa ad un processo per la sintesi di 1-(6-metilpiridin-3-il)-2-[(4-metilsulfonil)fenil]etanone, che comprende le seguenti operazioni: This and other purposes are achieved with the present invention, which relates to a process for the synthesis of 1- (6-methylpyridin-3-yl) -2 - [(4-methylsulfonyl) phenyl] ethanone, which comprises the following operations:
a) reazione tra 6-metilnicotinato di metile (II) e 4-(metiltio)benzilcianuro (III) a dare 3-(6-metilpiridin-3-il)-2-(4-metilsulfanilfenil)-3-osso-proprionitrile (IV): a) reaction between methyl 6-methylnicotinate (II) and 4- (methylthio) benzylcyanide (III) to give 3- (6-methylpyridin-3-yl) -2- (4-methylsulfanylphenyl) -3-oxo-propionitrile ( IV):
b) ossidazione del composto (IV) a dare 3-(6-metilpiridin-3-il)-2-(4-metilsulfonilfenil)-3-osso-proprionitrile (V): b) oxidation of compound (IV) to give 3- (6-methylpyridin-3-yl) -2- (4-methylsulfonylphenyl) -3-oxo-propionitrile (V):
c) idrolisi del gruppo ciano del composto (V) e successiva decarbossilazione termica a dare 1-(6-metilpiridin-3-il)-2-[(4-metilsulfonil)fenil]etanone (I): c) hydrolysis of the cyano group of compound (V) and subsequent thermal decarboxylation to give 1- (6-methylpyridin-3-yl) -2 - [(4-methylsulfonyl) phenyl] ethanone (I):
in cui l’intermedio (V) ottenuto nell’operazione b) non viene isolato, e la miscela ottenuta nell’operazione b) viene usata come tale nell’operazione c), di modo che dette operazioni b) e c) formano una sequenza continua di tre reazioni. in which the intermediate (V) obtained in operation b) is not isolated, and the mixture obtained in operation b) is used as such in operation c), so that said operations b) and c) they form a continuous sequence of three reactions.
Nel passaggio dal composto (V) al prodotto desiderato (I), viene formato l’acido carbossilico corrispondente al gruppo ciano di (V), che non viene isolato ma sottoposto direttamente a decarbossilazione termica. In the passage from compound (V) to the desired product (I), the carboxylic acid corresponding to the cyano group of (V) is formed, which is not isolated but directly subjected to thermal decarboxylation.
Il processo dell'invenzione passa attraverso la preparazione di intermedi differenti da quelli del processo di WO 2012/066570 A2; in particolare, nel processo dell’invenzione il passaggio di ossidazione (dell'intermedio (IV) precede il passaggio di idrolisi del gruppo ciano e decarbossilazione termica. Questo approccio sintetico consente di dover isolare solo il primo intermedio (IV), eseguendo poi la reazione di ossidazione a dare (V) e la successiva idrolisi e decarbossilazione a dare (I) senza la necessità di isolare l’intermedio (V). Gli inventori hanno trovato che operando secondo le modalità sopra descritte si ottiene il composto (I) desiderato con una purezza HPLC superiore a 99%, contro il 92,5% del processo noto, e quindi più idoneo all’impiego nei successivi passaggi di produzione del composto farmaceutico Etoricoxib. The process of the invention passes through the preparation of intermediates different from those of the process of WO 2012/066570 A2; in particular, in the process of the invention the oxidation step (of the intermediate (IV) precedes the hydrolysis step of the cyano group and thermal decarboxylation. This synthetic approach allows to isolate only the first intermediate (IV), then performing the oxidation reaction to give (V) and the subsequent hydrolysis and decarboxylation to give (I) without the need to isolate the intermediate (V). The inventors have found that by operating according to the methods described above, compound (I) is obtained desired with an HPLC purity higher than 99%, against 92.5% of the known process, and therefore more suitable for use in the subsequent production steps of the pharmaceutical compound Etoricoxib.
Descrizione dettagliata dell’invenzione Detailed description of the invention
La prima operazione del processo dell’invenzione, a), consiste nella reazione tra 6-metilnicotinato di metile (II) e 4-(metiltio)benzilcianuro (III) a dare 3-(6 metilpiridin-3-il)-2-(4-metilsulfanilfenil)-3-osso-proprionitrile (IV). The first step of the invention process, a), consists in the reaction between methyl 6-methylnicotinate (II) and 4- (methylthio) benzylcyanide (III) to give 3- (6 methylpyridine-3-yl) -2- (4-methylsulfanylphenyl) -3-oxo-propionitrile (IV).
La reazione viene preferibilmente condotta con un lieve eccesso stechiometrico di 6-metilnicotinato di metile (II) (per esempio, fino al 30% molare in più rispetto al cianuro (III)); in un solvente inerte, preferibilmente un idrocarburo aromatico; e in presenza di una base organica scelta tra un alcossido di sodio o potassio, eventualmente aggiunto sotto forma di soluzione in un solvente che à ̈ preferibilmente l’alcol corrispondente al radicale RO- dell’alcossido. The reaction is preferably carried out with a slight stoichiometric excess of methyl 6-methylnicotinate (II) (for example, up to 30% molar more than cyanide (III)); in an inert solvent, preferably an aromatic hydrocarbon; and in the presence of an organic base chosen from a sodium or potassium alkoxide, possibly added in the form of a solution in a solvent which is preferably the alcohol corresponding to the RO- radical of the alkoxide.
La reazione viene condotta ad una temperatura compresa tra circa 80 e 90 °C, per un tempo sufficiente ad eliminare per distillazione l’alcol impiegato, normalmente tra alcune ore e circa 12 ore. La reazione viene poi interrotta portando la temperatura ad un valore compreso tra 40 e 60 °C e aggiungendo un acido in eccesso molare rispetto alla base inizialmente impiegata e acqua distillata; l’acido può essere per esempio acido acetico. Infine, si raffredda a temperatura ambiente e l’intermedio precipitato viene filtrato e lavato con un solvente organico, e successivamente con acqua. The reaction is carried out at a temperature between about 80 and 90 ° C, for a time sufficient to eliminate the alcohol used by distillation, usually between a few hours and about 12 hours. The reaction is then stopped by bringing the temperature to a value between 40 and 60 ° C and adding an acid in molar excess with respect to the base initially used and distilled water; the acid can be for example acetic acid. Finally, it is cooled to room temperature and the intermediate precipitate is filtered and washed with an organic solvent, and subsequently with water.
Il prodotto 3-(6-metilpiridin-3-il)-2-(4-metilsulfanilfenil)-3-osso-proprionitrile (IV), ottenuto in forma di solido, non necessita di essere essiccato prima di impiegarlo nel passaggio successivo del processo. The product 3- (6-methylpyridin-3-yl) -2- (4-methylsulfanylphenyl) -3-oxo-propionitrile (IV), obtained in solid form, does not need to be dried before using it in the next step of the process .
Come detto, le operazioni b) e c) vengono svolte con continuità e senza isolare i vari prodotti intermedi che si formano. L’evitare l’isolamento degli intermedi comporta come vantaggi che il processo à ̈ più veloce, più economico e più sicuro. As mentioned, operations b) and c) are carried out continuously and without isolating the various intermediate products that are formed. Avoiding the isolation of the intermediates has the advantage that the process is faster, cheaper and safer.
Nell’operazione b), il composto (IV) viene ossidato a dare il corrispondente solfone, 3-(6-metilpiridin-3-il)-2-(4-metilsulfonilfenil)-3-osso-proprionitrile (V). In step b), compound (IV) is oxidized to give the corresponding sulphone, 3- (6-methylpyridin-3-yl) -2- (4-methylsulfonylphenyl) -3-oxo-propionitrile (V).
La reazione avviene preferibilmente in condizioni acide e in presenza di un blando catalizzatore di ossidazione (per esempio, tungstato di sodio); l’agente ossidante preferito à ̈ il perossido di idrogeno, H202. La reazione avviene a T ambiente e dura circa 6 ore. The reaction preferably takes place under acidic conditions and in the presence of a mild oxidation catalyst (for example, sodium tungstate); the preferred oxidizing agent is hydrogen peroxide, H202. The reaction takes place at room T and lasts about 6 hours.
Al completamento della reazione di ossidazione (che può essere monitorato per esempio con TLC), la miscela di reazione contenente l’intermedio (V) viene trattata, senza ulteriori lavorazioni, in condizioni adatte alla realizzazione dell’operazione c) del processo. Upon completion of the oxidation reaction (which can be monitored for example with TLC), the reaction mixture containing the intermediate (V) is treated, without further processing, in conditions suitable for carrying out step c) of the process.
Allo scopo, detta miscela viene versata in acido solforico al 96%, e il sistema viene scaldato a 100-130 °C per un’ora, ottenendo così l’idrolisi e la decarbossilazione del composto (V) a dare il prodotto desiderato (I). La reazione viene interrotta portando la temperatura del sistema a T ambiente ed aggiungendo una miscela di acqua ed una base, per esempio ammoniaca, per neutralizzare l’acido aggiunto in precedenza, oltre ad un solvente organico in cui il prodotto desiderato risulta essere insolubile (es. etile acetato). La massa precipitata così ottenuta viene poi raffreddata a temperatura ambiente per favorire la massima separazione (precipitazione) del prodotto solido dalla fase liquida; seguono le usuali procedure di filtrazione e lavaggio del precipitato prima con acqua e poi con il solvente organico usato in precedenza, ed infine essiccamento per ottenere il prodotto (I). For this purpose, said mixture is poured into 96% sulfuric acid, and the system is heated at 100-130 ° C for one hour, thus obtaining the hydrolysis and decarboxylation of the compound (V) to give the product desired (I). The reaction is stopped by bringing the system temperature to room T and adding a mixture of water and a base, for example ammonia, to neutralize the acid previously added, as well as an organic solvent in which the desired product is insoluble ( e.g. ethyl acetate). The precipitated mass thus obtained is then cooled to room temperature to favor the maximum separation (precipitation) of the solid product from the liquid phase; the usual procedures of filtration and washing of the precipitate follow, first with water and then with the organic solvent previously used, and finally drying to obtain the product (I).
Una volta formato, il composto (I) può essere trasformato in Etoricoxib con modalità note nel settore, per esempio secondo quanto descritto nella domanda di brevetto WO 98/03484 A1 e nel brevetto US 5.861.419, ottenendo un polimorfo del composto noto come Forma I dalla letteratura (si veda la domanda di brevetto internazionale WO 01/37833 A1). Once formed, compound (I) can be transformed into Etoricoxib with methods known in the sector, for example as described in patent application WO 98/03484 A1 and in US patent 5,861,419, obtaining a polymorph of the compound known as Forma I from the literature (see international patent application WO 01/37833 A1).
L’invenzione verrà ulteriormente illustrata dai seguenti esempi. The invention will be further illustrated by the following examples.
ESEMPIO 1 EXAMPLE 1
Preparazione di 3-(6-metilpiridin-3-il)-2-(4-metilsulfanilfenil)-3-osso-propionitrile. In un pallone si caricano 19,8 g di 6-metilnicotinato di metile (0,13 mol), 18,0 g di 4-(metiltio)benzilcianuro (0,11 mol), 150 g di toluene e 24 g di una soluzione al 30% in peso di metilato di sodio (CH3ONa) in metanolo (0,13 mol). Si scalda la massa a 80-90 °C e si mantiene a questa T per circa 12 ore, lasciando il sistema in distillazione per eliminare il metanolo che si libera. Preparation of 3- (6-methylpyridin-3-yl) -2- (4-methylsulfanylphenyl) -3-oxo-propionitrile. 19.8 g of methyl 6-methylnicotinate (0.13 mol), 18.0 g of 4- (methylthio) benzylcyanide (0.11 mol), 150 g of toluene and 24 g of a solution are placed in a flask 30% by weight of sodium methylate (CH3ONa) in methanol (0.13 mol). The mass is heated to 80-90 ° C and is maintained at this T for about 12 hours, leaving the system in distillation to eliminate the methanol which is released.
Si porta quindi a 40-60°C e si aggiungono 18 g dì acido acetico all’80% (0,24 mol), 36 g di acqua distillata e si raffredda a temperatura ambiente. Di seguito si filtra, lavando il prodotto raccolto sul filtro con 36 g di toluene e 36 g di acqua distillata. Dalla determinazione della perdita in peso, si calcola il corrispettivo prodotto secco ottenuto, 27,4 g di 3-(6-metilpiridin-3-il)-2-(4-metilsulfanilfenil)-3-ossopropionitrile, composto (IV), con una resa pari a 88,0% rispetto a 4-(metiltio)benzilcianuro. Il prodotto raccolto sul filtro viene utilizzato umido tal quale nella successiva fase del processo The mixture is then brought to 40-60 ° C and 18 g of 80% acetic acid (0.24 mol), 36 g of distilled water are added and it is cooled to room temperature. Then it is filtered, washing the product collected on the filter with 36 g of toluene and 36 g of distilled water. From the determination of the weight loss, the corresponding dry product obtained is calculated, 27.4 g of 3- (6-methylpyridin-3-yl) -2- (4-methylsulfanylphenyl) -3-oxopropionitrile, compound (IV), with a yield equal to 88.0% with respect to 4- (methylthio) benzylcyanide. The product collected on the filter is used wet as it is in the next phase of the process
ESEMPIO 2 EXAMPLE 2
Preparazione di 1 -(6-metilpiridin-3-il)-2-[(4-metilsulfonil)fenil]etanone. Preparation of 1 - (6-methylpyridin-3-yl) -2 - [(4-methylsulfonyl) phenyl] ethanone.
In un pallone si caricano il 3-(6-metilpiridin-3-il)-2-(4-metilsulfanilfenil)-3-ossopropionitrile umido ottenuto nell’esempio precedente (corrispondente a 27,4 g, 0,097 mol, di prodotto secco), 137 g di acido solforico al 50% in peso (0,70 mol) e 0,5 g di tungstato di sodio come catalizzatore di ossidazione. Operando a temperatura ambiente, si aggiungono15,0 g di perossido di idrogeno a 197 volumi (0,22 mol). Si mantiene il sistema a circa 25 °C per 6 ore, quindi si versa la massa di reazione in un altro pallone contenente a 100-130 °C 82,2 g di acido solforico al 96% in peso (0,805 mol). Si mantiene la massa a 100-130 °C per 1 ora, quindi si aggiungono 164 g di acqua distillata, 191 g di ammoniaca al 30% in peso (3,38 mol) e 82 g di acetato di etile. Wet 3- (6-methylpyridin-3-yl) -2- (4-methylsulfanylphenyl) -3-oxopropionitrile obtained in the previous example (corresponding to 27.4 g, 0.097 mol, of dry product ), 137 g of 50% by weight sulfuric acid (0.70 mol) and 0.5 g of sodium tungstate as oxidation catalyst. Operating at room temperature, 15.0 g of hydrogen peroxide at 197 volumes (0.22 mol) are added. The system is maintained at about 25 ° C for 6 hours, then the reaction mass is poured into another flask containing 82.2 g of sulfuric acid at 96% by weight (0.805 mol) at 100-130 ° C. The mass is kept at 100-130 ° C for 1 hour, then 164 g of distilled water, 191 g of ammonia at 30% by weight (3.38 mol) and 82 g of ethyl acetate are added.
Si lascia il sistema in agitazione a temperatura ambiente per circa 30’, quindi si filtra lavando il filtrato con 55,4 g di acqua distillata e 55,4 g di acetato di etile. The system is left under stirring at room temperature for about 30 ', then filtered by washing the filtrate with 55.4 g of distilled water and 55.4 g of ethyl acetate.
Si essicca il composto raccolto sul filtro, ottenendo 15,0 g di 1-(6-metilpiridin-3-il)-2-[(4-metilsulfonil)fenil]etanone, per una resa (complessive tre reazioni chimiche eseguite nella sequenza di operazioni b) e c) del processo) del 53,4%. L'analisi del prodotto mostra una purezza HPLC superiore al 99,0%. The compound collected on the filter is dried, obtaining 15.0 g of 1- (6-methylpyridin-3-yl) -2 - [(4-methylsulfonyl) phenyl] ethanone, for a yield (a total of three chemical reactions carried out in the sequence of transactions b) and c) of the process) of 53.4%. Product analysis shows HPLC purity greater than 99.0%.
Claims (13)
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|---|---|---|---|---|
| WO1999015503A2 (en) * | 1997-09-25 | 1999-04-01 | Merck & Co., Inc. | Process for making diaryl pyridines useful as cox-2 inhibitors |
| WO2001007410A1 (en) * | 1999-07-27 | 2001-02-01 | Lonza Ag | Process for preparing 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl) phenyl] ethanone |
| WO2001029004A1 (en) * | 1999-10-15 | 2001-04-26 | Zambon Group S.P.A. | Oxidation process for the preparation of intermediates useful in the synthesis of diarylpyridines |
| WO2001029003A1 (en) * | 1999-10-15 | 2001-04-26 | Zambon Group S.P.A. | Process for the preparation of 1-(6-methylpyridin-3-yl)-2-(4-methylthiophenyl)-ethanone and its use in the synthesis of diarylpyridines |
| US20020042375A1 (en) * | 2000-07-05 | 2002-04-11 | Heimbrook David C. | Method of treating cancer |
| WO2003051843A1 (en) * | 2001-12-19 | 2003-06-26 | Zambon Group S.P.A. | Oxidation process for the preparation of intermediates useful in the synthesis of diarylpyridines |
| WO2012066570A2 (en) * | 2010-11-15 | 2012-05-24 | Virdev Intermediates Pvt. Ltd. | A process for cyclooxygenase-2 selective inhibitor |
| EP2497767A1 (en) * | 2011-03-09 | 2012-09-12 | F.I.S. Fabbrica Italiana Sintetici S.p.A. | Improved process for preparing 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone, an intermediate of etoricoxib |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999015503A2 (en) * | 1997-09-25 | 1999-04-01 | Merck & Co., Inc. | Process for making diaryl pyridines useful as cox-2 inhibitors |
| WO2001007410A1 (en) * | 1999-07-27 | 2001-02-01 | Lonza Ag | Process for preparing 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl) phenyl] ethanone |
| WO2001029004A1 (en) * | 1999-10-15 | 2001-04-26 | Zambon Group S.P.A. | Oxidation process for the preparation of intermediates useful in the synthesis of diarylpyridines |
| WO2001029003A1 (en) * | 1999-10-15 | 2001-04-26 | Zambon Group S.P.A. | Process for the preparation of 1-(6-methylpyridin-3-yl)-2-(4-methylthiophenyl)-ethanone and its use in the synthesis of diarylpyridines |
| US20020042375A1 (en) * | 2000-07-05 | 2002-04-11 | Heimbrook David C. | Method of treating cancer |
| WO2003051843A1 (en) * | 2001-12-19 | 2003-06-26 | Zambon Group S.P.A. | Oxidation process for the preparation of intermediates useful in the synthesis of diarylpyridines |
| WO2012066570A2 (en) * | 2010-11-15 | 2012-05-24 | Virdev Intermediates Pvt. Ltd. | A process for cyclooxygenase-2 selective inhibitor |
| EP2497767A1 (en) * | 2011-03-09 | 2012-09-12 | F.I.S. Fabbrica Italiana Sintetici S.p.A. | Improved process for preparing 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone, an intermediate of etoricoxib |
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