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WO2008101614A1 - Procédé de production de 4-(3-hydroxy-3-méthyl-butoxy)-5-[4-(méthylsulfonyl)phényl]-2-arylpyridazin-3(2h)-ones - Google Patents

Procédé de production de 4-(3-hydroxy-3-méthyl-butoxy)-5-[4-(méthylsulfonyl)phényl]-2-arylpyridazin-3(2h)-ones Download PDF

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Publication number
WO2008101614A1
WO2008101614A1 PCT/EP2008/001041 EP2008001041W WO2008101614A1 WO 2008101614 A1 WO2008101614 A1 WO 2008101614A1 EP 2008001041 W EP2008001041 W EP 2008001041W WO 2008101614 A1 WO2008101614 A1 WO 2008101614A1
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formula
compound
fluorophenyl
xiii
methylthio
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PCT/EP2008/001041
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German (de)
English (en)
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Franz-Josef Mais
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Bayer Animal Health Gmbh
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Publication of WO2008101614A1 publication Critical patent/WO2008101614A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
    • C07D237/14—Oxygen atoms
    • C07D237/16—Two oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to an improved process for the preparation of 4- (3-hydroxy-3-methylbutoxy) -5- [4- (methylsulfonyl) phenyl] -2- (4-fluoro-phenyl) pyridazine-3 (2H) -one and closely related analogue, which is particularly suitable for production on an industrial scale.
  • aryl is phenyl, 4-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl or 2-fluorophenyl.
  • Compounds of formula I are of e.g. WO 99/10331 or WO 2000/024719. They are 5 selective inhibitors of cyclooxygenase-2 and they serve to control diseases, e.g. of inflammation-related pain, rheumatoid arthritis or osteoarthritis in humans and animals (warm-blooded animals).
  • the embodiment of the method differs in WO 2000/024719 or OPRD.
  • the reaction of the compound of the formula VIII to give the compound of the formula IX is carried out according to WO 2000/024719 by reacting the compound of the formula VIII with a THF solution of the alcoholate of 3-methyl-1,3-butanediol.
  • the alkoxide is prepared in situ by addition of NaH to a THF solution of 3-methyl-1,3-butanediol.
  • OPRD a detailed description is given for the same implementation.
  • As the base is reported for the production of the alcoholate of 3-methyl-l, 3-butanediol sodium hexamethyldisilazide and with limitations potassium hexamethyldisilazide or NaH.
  • the solvent used is THF and with restrictions toluene.
  • the reaction of the compound of the formula IX into the compound of the formula X is effected by Suzuki coupling of the compound of the formula IX with thioanisole boronic acid in ethanol as solvent, with potash as base and PdCl 2 (PPh 3 ) 2 as catalyst at 60 -65 0 C performed in 40-70min.
  • the same implementation is described in much greater detail in OPRD.
  • the catalysts described are the use of palladium (II) acetate in combination with triphenylphosphine or tris (o-tolyl) phosphines, of PdCl 2 (PPh 3 ) 2 or of palladium on carbon.
  • the base described is a mixture of potassium phosphate tribasic and potassium phosphate dibasic.
  • the solvent used is a mixture of isopropanol and water.
  • the reaction temperature is 70-75 0 C. - -
  • Oxone in aqueous acetone 30% aqueous hydrogen peroxide in ethyl acetate, peracetic acid in acetone, urea-hydrogen peroxide complex in acetone and sodium perborate in acetic acid.
  • the best yield is achieved with Oxone.
  • 30% aqueous hydrogen peroxide 88% yield was reported.
  • a disadvantage of this method is that the oxidizing agent in an amount of at least 3 equivalents (necessary only at least 2 equivalents), that is used in a significant excess.
  • oxone is very disadvantageous in the preferred oxidizing agent in that it involves enormous security risks for carrying out the reaction on an industrial scale.
  • volatile acetoxides such as dimethyldioxirane, form from the acetone solvent and are not controllable on an industrial scale when carrying out the processes.
  • a further disadvantage is that due to the high excess of oxidizing agent, an additional destruction agent for peroxides must be added to the batch after the end of the reaction and before product isolation.
  • sulfur-containing destruction means such as described in OPRD, additional impurities such as analytically very difficult to detect sulfur can be introduced into the final product. This is not acceptable pharmaceutically.
  • Ar is phenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl or 3,4-difluorophenyl, in which man
  • the method is both in the laboratory (vessel size up to 10 liters), as well as on a kilogram scale (vessel size up to 200 liters) and on an industrial scale easy and safe feasible, under technical scale to carry out the implementation in vessels from about 200 liters Size is understood.
  • the invention further relates to:
  • Ar is phenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl or 3,4-difluorophenyl,
  • step (b) of the reaction sequence described above the actual coupling reaction (XII-XIII) is preferably followed by a purification step in which the palladium is removed.
  • an inorganic sulfur-containing reducing agent is preferably used in combination with activated carbon. The invention therefore further relates to:
  • an inorganic sulfur D-containing reducing agent is used in combination with activated carbon.
  • the starting material of the formula XI to be used according to the invention can be prepared by methods known per se from mucobromic acid and an optionally substituted arylhydrazine or aniline. See, e.g. WO 99/10331 or WO 2000/024719) or DAS 1 086 238 or DAS 1420 01 1 or GB 881616 or K.H. Pilgram, G.E. Pollard, J. Heterocycl. Chem., 14, 1039 (1977) or F. Kuhelj et. al., Croat. Chem. Acta, 38 (1966), 299 or A. Bistrzycki, H. Simonis, Chem. Ber., 32 (1899), 534) or DOS 2526643 or F.A.J. Kerdesky et. al., Org. Proc.Res.Develop., 10, 512 (2006) or also CH 482 684.
  • the reaction of the compound of formula XI with the alcoholate of 3-methyl-l, 3-butanediol is usually carried out in solution.
  • the solvents used are cyclic aliphatic ethers such as THF, 2-methyltetrahydrofuran, dioxane, etc.
  • THF is used.
  • the amount of the total solvent to be used in the process (for example, the sum of THF in the template suspension and THF in the solution of the alcoholate of 3-methyl-1,3-butanediol and possibly flushing amounts) is usually from 3 to 15 based on the compound of the formula XI , preferably 3.5 to 10, particularly preferably 4 to 6, in each case in kg of solvent per kg of the compound of the formula XI.
  • tertiary alkoxide As a tertiary alkoxide according to the invention, the use of a lithium, sodium or potassium alcoholate of a tertiary alcohol is possible. Preference is given to the use of a sodium alcoholate.
  • the term tertiary alcohol may according to the invention, in particular z. B. tert-butanol, 2-methyl-2-butanol, 3,7-dimethyl-3-octanol mean. Of these, preferred are tert-butanol and 2-methyl-2-butanol, particularly preferably tert-butanol.
  • the tertiary alcoholates can be used as a solid or as a solution in the process.
  • the use of a solution in the abovementioned cyclic ethers as solvent, in particular a THF solution for example the sodium alcoholates of 2-methyl-2-butanol or especially of tert-butanol
  • THF solution for example the sodium alcoholates of 2-methyl-2
  • a solution of the alcoholate of the tertiary alcohol with the 3-methyl-l, 3-butanediol is brought together.
  • the temperature in this process is according to the invention 0-50 0 C, preferably, 10-40 0 C, particularly preferably 20- 35 ° C.
  • the amount of 3-methyl-l, 3-butanediol based on the alcoholate of the tertiary alcohol is preferably chosen so that 3-methyl-l, 3-butanediol is present in a slight excess.
  • 2.0 to 1.0 equivalents of 3-methyl-1,3-butanediol, based on the alcoholate of the tertiary alcohol are preferably 1.5 to 1.02 equivalents, more preferably 1.2 to 1.05 equivalents.
  • the solution of the alcoholate of 3-methyl-l, 3-butanediol is metered into the reaction mixture of the compound of formula XI, preferably it is a suspension in a cyclic aliphatic ether, in particular in THF.
  • the temperature of this process is preferably from 0 to 50 0 C, particularly preferably at 10-40 0 C, especially at 20-30 0 C.
  • the amount of alkoxide of 3-methyl-l, 3-butanediol is set according to the invention by the amount of alkoxide used of the tertiary alcohol. Both amounts are identical by the use of an excess of 3-methyl-l, 3-butanediol in their molar amounts.
  • the molar amount of alkoxide of 3-methyl-l, 3-butanediol based on compound of formula XI is preferably 1, 0 to 1.2, more preferably 1.03 to 1.12, in particular 1.06 to 1.09, respectively expressed in equivalents of alkoxide, based on equivalents of the compound of formula XI.
  • a reaction mixture which contains the compound of the formula XII, preferably in solution.
  • sodium bromide which usually precipitates.
  • the sodium bromide is separated.
  • the reaction suspension is mixed with water and the sodium bromide is removed by dissolving in and separating the water phase.
  • the amount of water to be used according to the invention is usually from 1.2 to 0.6 kg of water per kg of the compound of the formula XI, preferably from 1.1 to 0.7 kg, particularly preferably from 1.0 to 0.8 kg.
  • salt the usual e.g. inorganic salts such as the alkali, ammonium or alkaline earth salts of hydrohalides, sulfuric or phosphoric acid, etc. are used. However, the use of salt is not preferred.
  • reaction component for the reaction of the compound of formula XII to the compound of formula XIII (hereinafter referred to as Suzuki coupling) to.
  • This reaction component is 4- (methylthio) phenylboronic acid or a 4- (methylthio) phenylboronic acid ester.
  • Suitable 4- (methylthio) phenylboronic acid and boronic esters are preferably those of the formula XIV,
  • R is hydrogen or CpC ö alkyl or both radicals R (-RR-) together for the
  • R represents hydrogen, methyl, ethyl, propyl, isopropyl and RR pinacolyl (ie, CMe 2 -CMe 2 -). More preferably R is hydrogen (4- (methylthio) phenylboronic acid).
  • the preferred amount of boronic acid or boronic acid ester used is between D 1, 5 and 0.8 equivalents based on the compound of formula XI, more preferably from 1, 25 to 0.9, in particular from 1.1 to 0.95.
  • water is preferably added to the reaction mixture to carry out the Suzuki coupling.
  • water is preferably added to the reaction mixture to carry out the Suzuki coupling.
  • dosed 1, 5 to 7.5 kg of water per kg of compound of formula XI, preferably 2 to 6 kg, more preferably 2 to 4 kg of water.
  • the Suzuki coupling is carried out in the presence of a base.
  • a base for this purpose, according to the invention, the customary bases known in the chemical literature for a Suzuki reaction, such as the alkali metal salts of carbonic or phosphoric acid, can be used.
  • bases which may be mentioned are D: sodium and potassium carbonate, sodium and potassium bicarbonate, sodium and potassium phosphate, sodium and potassium hydrogen phosphate, etc. It is also possible to use mixtures of these bases.
  • the preferred bases are sodium and potassium carbonate, more preferably sodium carbonate.
  • the amount of base in the use of the carbonates based on the compound of the formula XI is preferably 4.0 to 1.0 mol per mol of the compound of the formula XI, particularly preferably 3.0 to 1.25 mol, in particular 2.5 to 1.5 mol.
  • Suitable catalysts according to the invention are the catalysts D customary for the Suzuki coupling. These catalysts are palladium compounds to which optionally one or more phosphine ligands can be added. Examples of the palladium compound are: Pd (OAc) 2 , Pd on activated carbon, PdCl 2 , PdCl 2 (PPh 3 ) 2 , Pd (PPh 3 ) 4 , PdCl 2 (dppf), etc.
  • phosphine ligands are: triphenylphosphine , Tris (o-tolyl) phosphine, tris (2) furyl) phosphine, 1, 2-bis (diphenylphosphino) ethane, 1, 3-bis (diphenylphosphino) propane, 1,1 '- bis (diphenylphosphino) ferrocene, etc.
  • a combination of Pd (O Ac) 2 and triphenylphosphine is preferred ,
  • the molar ratio of Pd (O Ac) 2 to triphenylphosphine is preferably 1: 1 to 1: 6, more preferably 1: 1, 5 to 1: 4, in particular 1: 1.8 to I: 2, ⁇ 5.
  • the amount of catalyst used is as low as possible in order to minimize the contamination of the product with palladium. In principle, however, it is possible to use high amounts of catalyst of 10 mol% of palladium compound or more, based on the starting material of the formula XI. This is not preferred.
  • the Suzuki coupling is carried out in a temperature range from room temperature to 100 0 C, wherein at temperatures above the boiling point of the reaction mixture, the reaction is optionally carried out under pressure. Preference is given to carrying out of 40 0 C up to reflux temperature, more preferably is an implementation with stirring under reflux.
  • the reaction time is such that the compound of formula XII is completely or almost completely reacted. After complete or almost complete reaction of the compound of the formula XII, the compound of the formula XIII is now present in the reaction mixture, preferably in solution. Now, if necessary, the solvent is changed for the next reaction.
  • the procedure is as follows: To isolate this compound, the aqueous phase of the biphasic reaction mixture is first separated off and the solvent, for example THF, is then replaced by an aromatic solvent by carrying out a distillative solvent exchange in the manner known per se.
  • the solvent for example THF
  • the aromatic solvent for example THF
  • the original solvent is largely distilled off
  • the aromatic Kirksmitttel sets and distilled residues of the original solvent and a portion of the added aromatic solvent.
  • aromatic solvent it is possible according to the invention to use mono- or polysubstituted benzene derivatives, for example C 1 -C 6 -alkylbenzene, halogenobenzene, xylene, or halogen-benzene optionally substituted by C 1 -C 4 -alkyl.
  • Preferred aromatic solvents are toluene, ethylbenzene, cumene, fluorobenzene, chlorobenzene, ortho- or meta- or para-xylene, ortho- or meta- or para-chlorotoluene, ortho- or meta- or para-fluorobenzene, tetralin, mesitylene. Particularly preferred are toluene, ethylbenzene, ortho or meta or para-xylene.
  • activated carbon commercial activated carbons based on e.g. Peat, coconut shells, animal bones or other vegetable or animal raw materials.
  • the activated carbon can be used in dry or water-moist form.
  • the following may be used as the reducing agent containing inorganic sulfur: bisulfites, metabisulfites, dithionites, thiosulfates, sulfites, in particular the alkali metals, preferably of sodium or of potassium.
  • the use of sodium bisulfite, sodium metabisulfite, sodium sulfite and potassium sulfite is preferred according to the invention; the use of sodium bisulfite, sodium metabisulfite or sodium sulfite is particularly preferred.
  • the addition of the inorganic sulfur-containing reducing agent may be dry or in the form of aqueous solution. It is inventively preferred that a certain amount of water is introduced into the reaction mixture together with the addition of the activated carbon and the reducing agent containing inorganic sulfur.
  • the water can be added as such, in the form of a water-moist activated carbon or in the form of an aqueous solution of an inorganic sulfur-containing reducing agent. According to the invention, all three options are preferred.
  • the amount of activated carbon used usually ranges from 0.25 to 25% by weight, based on the starting material of the formula XI, preferably in a range from 0.5 to 15% by weight, especially preferably in a range of 1 to 10 wt .-%.
  • the amount of water to be used usually ranges from 0.25 to 20% by weight based on the starting material of the formula XI, preferably in a range of 0.5 to 15 - -
  • the weight ratio of activated carbon to water thereby usually moves in a range of 10 to 0.5, preferably in a range of 5 to 0.75, especially preferably in a range of 2 to 0.9.
  • the amount of inorganic sulfur-containing reducing agent to be used in the present invention usually ranges from 0.1 to 25% by weight based on the starting material of the formula XI, preferably from 0.5 to 15% by weight. more preferably in a range of 1 to 10% by weight.
  • the weight ratio of activated carbon to inorganic sulfur-containing reducing agent usually ranges from 10 to 0.1, preferably from 7.5 to 0.25, more preferably from 5 to 0.5.
  • the added activated carbon is removed from the solution together with the water and the inorganic sulfur-containing reducing agent after the palladium-removing action has been exerted, e.g. by filtration.
  • the compound of formula XIII can be isolated, for example by crystallization, filtration and drying.
  • the compound of formula XIII thus obtained can be further purified by additional crystallization.
  • this crystallization can be carried out without addition, with addition of dry activated carbon, water-moist activated carbon or activated carbon plus water or a mixture of activated carbon plus water plus inorganic sulfur-containing reducing agent as described above.
  • suitable solvents for this crystallization are: methanol, ethanol, isopropanol, methanol / water, ethanol / water, isopropanol / water, ethyl acetate, ethyl acetate / hydrocarbon (such as pentanes, hexanes, methylcyclohexane, heptanes, octanes, etc.
  • the optionally purified compound of formula XIII is then oxidized by means of hydrogen peroxide as the oxidizing agent to the compound of formula I.
  • any available quality can be used as hydrogen peroxide in the process according to the invention.
  • the use of highly concentrated hydrogen peroxide is only possible under extremely high risks combined with extremely high security costs. Therefore, the use of highly concentrated hydrogen peroxide in practice, especially on an industrial scale, is not preferred for safety reasons. Therefore, according to the invention, preference is given to using a mixture of hydrogen peroxide and water with a weight fraction of hydrogen peroxide of from 1 to 45%, preferably from 5 to 40%, particularly preferably from 20 to 37%.
  • the amount of hydrogen peroxide to be used according to the invention is 2.0 to 3.5 equivalents, preferably 2.0 to 2.75 equivalents, particularly preferably 2.0 to 2.5 equivalents.
  • a water-miscible or at least partially water-miscible alcohol having 1 to 4 carbon atoms is preferably used according to the invention.
  • solvents include: methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, isobutanol, tert. Butanol. Preference is given to methanol, ethanol, propanol and isopropanol.
  • the amount of solvent to be employed in the reaction of the compound of the formula XIII with the compound of the formula I is usually from 2 to 50 parts by weight of solvent per part by weight of starting material of the compound of the formula XIII, preferably from 2.5 to 25% by weight , more preferably 2.5 to 10 parts by weight.
  • water may be added as a cosolvent.
  • the amount of water according to the invention is from 0.01 to 1 parts by weight, preferably from 0.02 to 0.5 parts by weight, more preferably from 0.025 to 0.2 parts by weight, based on the alcohol used.
  • the oxidation according to the invention is carried out in the presence of catalysts.
  • catalysts which can be used according to the invention include the following: sodium tungstate,
  • Preferred is sodium tungstate.
  • the sodium tungstate can be used in the form of sodium tungstate dihydrate.
  • the amount of catalyst to be used according to the invention should not be too high in order to avoid high loading of the product of formula I by e.g. To avoid tungsten. In principle, however, it is also possible to add very high amounts of 10 mol% or more of catalyst.
  • the catalyst is preferably added in 0.05 to 5 mol%, particularly preferably in 0.1 to 2.5 mol%, in particular in 0.2 to 1.5 mol%, based on the compound of the formula XIII to be employed.
  • the pH of the reaction mixture is preferably set in the acidic range.
  • a small amount of a mineral acid is added as such or in the form of an aqueous solution.
  • Sulfuric acid or phosphoric acid, etc. may be mentioned as mineral acid, etc.
  • Preferred is sulfuric acid, particularly preferred is an aqueous solution of sulfuric acid with a sulfuric acid content of 10 to 50 wt .-%.
  • the amount of acid to be used is usually 0.005 to 0.1 equivalent, based on the compound of the formula XIII to be used, more preferably 0.01 to 0.05 equivalent, particularly preferably 0.02 to 0.035.
  • the compound of formula XIII in the alcohol is optionally dissolved together with the water, the catalyst and the acid and optionally heated to the reaction temperature. Then, the hydrogen peroxide is added over a period of time and the exothermic heat of reaction is removed by cooling.
  • the reaction temperature of the invention is generally between 0 0 C and the boiling point of the alcohol, but is preferably from 20 to 65 ° C, more preferably 40-60 0 C.
  • reaction mixture After completion of the reaction, the reaction mixture can be cooled.
  • the product of the formula I is isolated, usually it crystallizes out and is replaced by z.
  • the reaction mixture may be diluted with additional water after or before cooling, and then the crystallized product of formula I is isolated.
  • the product of formula I can be recrystallized. This may be out Ethyl acetate / hydrocarbon (such as pentanes, hexanes, methylcyclohexane, heptanes, octanes, etc. or derived from the petroleum distillation hydrocarbon mixtures having a boiling range of 30 to 140 0 C [special gasoline, benzine, ligroins, etc.]) optionally with the addition of activated carbon or from water / Alcohol (such as methanol, ethanol isopropanol) optionally with the addition of activated carbon.
  • Ethyl acetate / hydrocarbon such as pentanes, hexanes, methylcyclohexane, heptanes, octanes, etc. or derived from the petroleum distillation hydrocarbon mixtures having a boiling range of 30 to 140 0 C [special gasoline, benzine, ligroins, etc.]
  • activated carbon or from water / Alcohol (such
  • the internal temperature was kept at about room temperature by cooling. It was rinsed with 34 parts by weight of THF, the total mixture was stirred for 15 min at room temperature and then metered 84 parts by weight of cold water. After brief stirring, the water phase was allowed to settle and separated.
  • the activated carbon was filtered hot and washed with 26 parts by weight of hot toluene.
  • the combined filtrates were cooled to 0-5 0 C and the precipitated solid was filtered off, washed with a total of 89 parts by weight of toluene and dried in vacuo at 45-50 0 C.
  • Example 1 The procedure of Example 1, part Ia) and part Ib) was repeated eight times on an industrial scale.
  • the resulting products of formula XIII were purified in six further runs on an industrial scale according to Example 3. The following contents were obtained
  • Example 3 The procedure of Example 3 was repeated except that instead of the product of Example 1, the product of the formula XIII from Example 3 was used.
  • the weight was 85.2 parts by weight, which corresponds to a yield of 85.2% of theory. corresponded.
  • the palladium content was 27 ppm.
  • Example 1 1 The procedure of Example 1 1 was repeated eight times on an industrial scale, the
  • Example 13 The slightly lower yield in Example 13 is due to the removal of a larger sample for testing purposes before final weighing.

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Abstract

La présente invention concerne un procédé amélioré de production de 4-(3-hydroxy-3-méthylbutoxy)-5-[4-(méthylsulfonyl)phényl]-2-(4-fluorophényl)pyridazin-3(2H)-one et d'analogues étroitement apparentés, ce procédé étant particulièrement adapté à une production à l'échelle industrielle.
PCT/EP2008/001041 2007-02-23 2008-02-12 Procédé de production de 4-(3-hydroxy-3-méthyl-butoxy)-5-[4-(méthylsulfonyl)phényl]-2-arylpyridazin-3(2h)-ones WO2008101614A1 (fr)

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DE102007008839.8 2007-02-23
DE102007008839A DE102007008839A1 (de) 2007-02-23 2007-02-23 Verfahren zur Herstellung von 4-(3-Hydroxy-3-methyl-butoxy)-5-[4-(methylsulfonyl)phenyl]-2-arylpyridazin-3(2H)-onen

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000024719A1 (fr) * 1998-10-27 2000-05-04 Abbott Laboratories Inhibiteurs de la biosynthese de la prostaglandine endoperoxyde h synthase

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL252908A (fr) 1959-06-23
CH482684A (de) 1967-01-02 1969-12-15 Sandoz Ag Verfahren zur Herstellung eines neuen Herbicids
WO1999010331A1 (fr) 1997-08-22 1999-03-04 Abbott Laboratories Arylpyridazinones inhibitrices de la biosynthese de la prostaglandine endoperoxyde h synthase

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000024719A1 (fr) * 1998-10-27 2000-05-04 Abbott Laboratories Inhibiteurs de la biosynthese de la prostaglandine endoperoxyde h synthase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
F. A. J. KERDESKY ET AL: "An Efficient Multikilogram Synthesis of ABT-963: A Selective COX-2 inhibitor", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 10, 2006, pages 512 - 517, XP002484415 *

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