WO1998024747A1

WO1998024747A1 - A process for the preparation of nabumetone

Info

Publication number: WO1998024747A1
Application number: PCT/EP1997/006680
Authority: WO
Inventors: Renzo Rossi; Graziano Castaldi; Antonio Tarquini; Catia Mastrangeli
Original assignee: Recordati S.A. Chemical And Pharmaceutical Company
Priority date: 1996-12-03
Filing date: 1997-12-01
Publication date: 1998-06-11
Also published as: AU5656698A

Abstract

A process for the preparation of nabumetone by means of a procedure involving the introduction, in a single step, of the 4 carbons aliphatic chain on the naphthalene ring, starting from 6-bromo-2-naphthol or from 2-bromo-6-methoxynaphthalene.

Description

A PROCESS FOR THE PREPARATION OF NABUMETONE

The present invention relates to a novel process for the preparation of 4- ( 6-methoxy-2-naphthyl )-2- butanone (nabumetone).

Nabumetone is a known product with antiinflammatory activity.

A number of methods for the preparation of nabumetone are known: for example, 2-bromo-6- methoxynaphthalene can be reacted with 2-hydroxy-l- butene to give nabumetone, or with methyl vinyl ketone to obtain the α ,β-unsaturated keto intermediate which, yields nabumetone by selective hydrogenation of the double bond. The same α ,β-unsaturated intermediate can be obtained from 2-formyl-6-methoxynaphthalene by reaction with acetone or acetyl acetone. Still another synthetic route involves the reaction of 2-acetyl-6-methoxy-naphthalene with ethyl acetate and the subsequent selective reduction of the resulting β- diketo (keto-enol) derivative.

Anyhow, the need for alternative procedures easily providing nabumetone in a pure form is particularly felt.

The process of the present invention allows to prepare nabumetone by means of a procedure involving the introduction, in a single step, of the 4 carbons aliphatic chain on the naphthalene ring, starting from 6-bromo-2-naphthol or from 2-bromo-6-methoxynaphthalene (see Scheme 1 below).

The process of the invention comprises the functionalization of 6-bromo-2-naphthol (la) or of 2- bromo-6-methoxynaphthalene (lb) with 3-butyn-2-ol through an organometallic reaction catalysed by palladium(O) and copper(I).

The process of the invention shown in the following

Scheme 1

Nabumetone comprises :

1. Alkylation of (la) or (lb) to give respectively the compounds 4- ( 6-hydroxy-2-naphthyl )-butyn-2-ol (Ila) or 4-(6-methoxy-2-naphthyl)-butyn-2-ol (lib) by reaction with 3-butγn-2-ol carried out in the simultaneous presence of palladium(O) and copper(I), as reported in the following Scheme 2.

Scheme 2

RO

Cla) R=H (Ila) R=H (lb) R=Me (lib) R=Me

wherein Pd(O) means palladium at the oxidation state 0, both at the elementary state (metal, cluster, etc.) and supported (for example on charcoal) in the presence of suitable ligands or in the form of complex. Among the most common ligands, phosphorous( III ) , nitrogen( III ) or arsenic(III) derivatives are preferred, such as triphenylphosphine , triphenylarsine or tetramethyletyle- nediamine .

Non limiting examples of the palladium complexes are the following: bis- ( triphenylphosphine )-dichloro complex , bis-( tributylphosphine )-dichloro complex, di-allγltriphenylphosphine-dichloro complex , tetrakis-( triphenylphosphine ) complex, triphenylphosphine-piperidine-dichloro complex , bis- (triphenylphosphine ) -diacetate complex, 2 , 4-pentanedione complex,

1 , 2-bis-( diphenylphosphine ) -ethane complex, wherein Cu(I) means copper salts at the oxidation state I, for example cuprous oxide, cuprous chloride, cuprous bromide, cuprous iodide, cuprous acetate, etc. The reaction is carried out preferably in the simultaneous presence of Pd/C, a phosphine ligand and a

Cu(I) salt in Pd:ligand:Cu molar ratios ranging from

1:4:2 to 0.5:2:0.5, preferably 1:3:1. The molar amount of palladium used is generally from 0.01 to 0.05 per mole of compounds (I), preferably 0.02.

The reaction is always carried out in the presence of a water amount ranging from 1 to 10 volumes per volume of compound (la) or (lb) loaded, and of a protic polar solvent, in particular water-miscible alcohols (such as ethanol, ethanol, isopropanol, 2-methoxy-l- propanol), in amounts ranging from 1 to 5 volumes per volume of compound (la) or (lb), at a temperature ranging from 20 to 150°C, preferably from 60 to 90°C. The reaction is carried out using a 3-butyn-2-ol molar amount ranging from 1 to 2 equivalents per equivalent of compound (la) or (lb), preferably from 1.2 to 1.5, and in the presence of a base molar amount ranging from 1 to 2 equivalents, preferably from 1.2 to 1.5. "Bases" means inorganic bases such as hydroxides, oxides, alkali metal carbonates and hydrogen carbonates such as sodium, potassium, lithium, or tertiary amine organic bases such as triethylamine , diisopropylethyla- mine, N-methylmorpholine , diazabicyclooctane and the like.

Compounds (II) are generally obtained in yields >80% after filtration of the reaction mixture, treatment of the solution with aqueous ammonia buffer at pH 8, cooling of the organic phase, filtration and drying. Alternatively, they can be obtained by treatment with aqueous ammonia buffer at pH 8, extraction with an organic solvent (such as toluene) and evaporation of the solvent (see the following Examples). Compound (Ila) is transformed into (lib) by ethylation with usual ethylating agents such as dimethylsulfate , methyl iodide and the like. Compound (lib), if necessary, can be purified by crystallization from aliphatic hydrocarbon solvents such as n-hexane, n-heptane, ligroins and the like.

2. Partial or total hydrogenation of compound (lib): a) Partial hydrogenation of the solution containing compound (lib) from the above step without need for a further addition of catalyst, to give 4-(6- methoxy-2-naphthyl )-buten-2-ol (Illb). The reaction is shown in Scheme 3a hereinbelow.

Scheme 3a

The hydrogenation reaction is usually carried out directly on the organic solution of compound (lib) from the first step, under hydrogen atmosphere and a pressure ranging from 1 to 10 atm (preferably 1 to 5 atm) and at a temperature ranging from 20 to 60°C (preferably 20 to 40°C) .

Surprisingly, the reduction carried out on the solution of compound (lib) from the first step, without removing the catalyst, gives selectively the partial hydrogenation product (Illb), contrary to what takes place when reduction is carried^' out on the isolated compound (lib). In this case, in fact, intermediate 4- ( 6-methoxy-2-naphthyl )-butan-2-ol is obtained which has to be oxidized to nabumetone, as it cannot isomerize.

Compound (Illb) is usually obtained by filtration of the catalyst and evaporation of the solvent. If necessary, the product is purified by crystallization or chromatography on silica gel (see Examples ) . b) Total hydrogenation of compound (lib), preferably catalysed by palladium(0)-on-charcoal , to give 4- ( 6-methoxy-2-naphthyl )-butan-2-ol (Ilia). The reaction is shown in Scheme 3b hereinbelow.

Scheme 3b

(lib) (Ilia)

The hydrogenation reaction is usually carried out in the presence of a palladium(0 )-on-charcoal catalyst in molar amounts ranging from 0.01 to 0.1 per mole of compound (lib) (preferably 0.02 to 0.05) in the presence of a solvent, under hydrogen atmosphere and a pressure ranging from 1 to 10 atm (preferably 1 to 5 atm) and at a temperature ranging from 20 to 120°C (preferably 20 to 40°C). "Solvents" mean alcohols (methanol, ethanol, isopropanol, n-butanol, etc.), aromatic hydrocarbons (toluene, xylene, etc.), esters (ethyl acetate, butyl acetate, etc.) which are used in amounts ranging from 1 to 10 volumes (preferably 2 to 5 ) per volume of compound (lib).

Compound (Ilia) is usually obtained by filtration of the catalyst and evaporation of the solvent. If necessary, the product is purified by crystallization or chromatography on silica gel (see Examples). 3a) Isomerization of (Illb) to nabumetone by use of catalysts of palladium( II ) (Coll. Czechoslov. Chem.

Comm. 1972, 37, 460), rhodium (I) (J. Org . Chem.

1980. 45, 2269), ruthenium (III) (J. Chem. Soc .

Chem. Comm. 1980. 594) and ruthenium( II )

(Tetrahedron Lett. 1993, 34, 5459), according to the following scheme:

Scheme 4a

(Illb) Nabumetone

"Catalyst" means derivatives of the above cited metals at various oxidation states in the form of salts, optionally in the presence of suitable ligands, or of complexes. Among the most common ligands, phosphorous (III) derivatives are meant, such as triphenylphosphine, tributylphosphine and the other ligands already cited with regard to the palladium catalyst.

The reaction is carried out in the presence of a catalyst (preferably based on ruthenium( III ) , such as ruthenium trichloride, both dry and hydrated), in amounts ranging from 0.005 to 0.1 moles per mole of substrate, preferably from 0.01 to 0.05. The reaction is carried out also in the presence of a base, in amounts ranging from 0.01 to 0.1 moles per mole of substrate, preferably from 0.01 to 0.05. Bases mean inorganic bases such as hydroxides, oxides, alkali metal carbonates and bicarbonates such as sodium, potassium, lithium or tertiary amine organic bases such as triethylamine , diisopropylethylamine, N-methylmorpholine , diazabicyclo- octane, etc.

Alcohols (such as isopropanol, l-methoxy-2- propanol, etc.), ethers (such as tetrahydrofuran, dimethoxyethane , etc.), amides (such as dimethylforma- mide, dimethylacetamide , N-methylpyrrolidone ) and ketones (such as acetone, methyl ethyl ketone, etc.) are used as reaction solvents in amounts ranging from 1 to 5 volumes per volume of substrate and at temperatures ranging from 50 to 150°C, preferably from 60 to 120°C.

The reaction provides nabumetone in yields ∑ 95% starting from (Illb). The final product is recovered by filtration of the catalyst and evaporation of the solvent and it is purified by crystallization or chromatography on silica gel.

3b) Oxidation of (Ilia) to nabumetone by conventional procedures described in M. Hudlicky, Oxidations, in

Organic Chemistry, ACS Monograph 186 - Washington,

DC (1990) and in the references cited therein, which comprise the use of Mn0₂ , KMnO^ , Ni-Raney,

DMSO-(COCl)₂, 0₂/PdCl₂, 0₂ , 0₂/Pt0₂, peracids (for example -chloroperbenzoic ) , perborates, percarbonates , Br₂, NaC10₄, CrC (also in the form of complexes), Al(OiPr ) ₂/acetone , etc. (Scheme 4b).

The oxidation is preferably performed using aluminium isopropoxide in amounts ranging from 0.1 to 1 equivalent per equivalent of (III), in the presence of a ketone or of a aldehyde, preferably cyclohexanone or benzaldehyde , in the presence or in the absence of a hydrocarbon solvent, preferably toluene or xylene. The reaction is generally carried out at a temperature ranging from 80° to 150°C, preferably from 100° to 120°C. Nabumetone is obtained by filtration of the mixture, evaporation of the volatile components and crystallization of the residue from alcohols, preferably ethanol .

Scheme 4b

(Ilia) Nabumetone

The invention is further illustrated by the following Examples.

Example 1: preparation of 4-( 6-methoxy-2-naphthyl )- butyn-2-ol (lib)

A mixture of 2-bromo-6-methoxynaphthalene (lb) (50 g, 211 moles), 10% Pd/C (4.5 g, 4.2 moles), cuprous iodide (1.6 g, 8.4 moles), triphenylphosphine (2.9 g, 12.7 moles), potassium carbonate (58 g, 422 moles), dispersed in l-methoxy-2-propanol (50 ml) and water (180 ml), is kept under stirring and inert atmosphere (nitrogen) at room temperature for 30 minutes. The mixture is then added in about 20 minutes with 55% aqueous 3-butyn-2-ol (42 ml, 316 moles) heated to the reflux temperature (90-95°C) until completion, (about 2 hours), cooled at 25°C, diluted with l-methoxy-2- propanol (500 ml) and filtered through Celite. The filtrate is added in 30 minutes with a mixture of 25% ammonia (100 ml) and an ammonium chloride saturated solution (100 ml). The mixture is stirred at room temperature for about 3 hours, filtered and the filtered product is washed with water. Upon drying under vacuum,

(lib) is obtained (46 g, 207 moles, 98% yield). M.p.= 83-85°C.

^^■H NMR (CDC1₃, delta in ppm): 1.57 (d, 3H); 1.70 (broad,

1H); 3.92 (s, 3H); 4.80 (m, 1H ) ; 7.1-7.9 (m, aromatic,

6H) .

Mass-EI m/e (%) 226 (M⁺), 211, 183, 168, 1521 139. Example 2: preparation of (lib)

A mixture of 2-bromo-6-methoxynaphthalene (lb) (5 g, 21.1 moles), 10% Pd/C (0.45 g, 0.42 moles), cuprous bromide (0.06 g, 0.42 moles), triphenylphosphine (0.29 g, 1.27 moles), potassium carbonate (5.8 g, 42.2 moles) dispersed in l-methoxy-2-propanol (5 ml) and water (18 ml) is stirred under inert atmosphere (nitrogen) at room temperature for 30 minutes. The mixture is then added in about 20 minutes with 55% aqueous 3-butyn-2-ol (4.2 ml, 31.6 moles), heated to reflux (90-95°C) until completion (about 2 hours), cooled at 25°C, diluted with 1-methoxy- 2-propanol (50 ml) and filtered through Celite. The filtrate is added in 30 minutes with a mixture of 25% ammonia (10 ml) and an ammonium chloride saturated solution (100 ml). The mixture is stirred at room temperature for about 3 hours, filtered and the filtered product is washed with water. Upon drying under vacuum, (lib) is obtained (4 g, 17.7 moles, 84% yield). Example 3: preparation of (lib)

A mixture of 2-bromo-6-methoxynaphthalene (5 g, 21.1 moles), 10% Pd/C (0.45 g, 0.42 moles), cuprous oxide (0.06 g, 0.42 moles), triphenylphosphine (0.29 g, 1.27 moles), potassium carbonate (5.8 g, 42.2 moles), dispersed in l-methoxy-2-propanol (50 ml) and water (180 ml) is stirred under inert atmosphere (nitrogen) at room temperature for 30 minutes. The mixture is then added in about 20 minutes with 55% aqueous 3-butyn-2-ol (4.2 ml,

31.6 moles), heated to reflux temperature (90-95°C) until completion (about 2 hours), cooled at 25°C, diluted with l-methoxy-2-propanol (50 ml) and filtered through Celite. The filtrate is added in 30 minutes with a mixture of 25% ammonia (10 ml) and an ammonium chloride saturated solution (10 ml). The mixture is stirred at room temperature for about 3 hours, filtered and the filtered product is washed with water. Upon drying under vacuum, (lib) is obtained (4 g, 17.7 moles, 84% yield) .

Example 4: preparation of (lib)

A mixture of 2-bromo-6-methoxynaphthalene (5 g, 21.1 moles), 10% Pd/C (0.45 g, 0.42 moles), cuprous iodide (0.08 g, 0.42 moles), triphenylphosphine (0.29 g, 1.27 moles), potassium carbonate (5.8 g, 42.2 moles) dispersed in isopropanol (5 ml) and water (18 ml) is stirred under inert atmosphere (nitrogen) at room temperature for 30 minutes. The mixture is then added in about 20 minutes with 55% aqueous 3-butyn-2-ol (4.2 ml, 31.6 moles), heated to reflux temperature (80-85°C) until completion (about 2 hours), cooled at 25°C, diluted with isopropanol (50 ml) and filtered through Celite. The filtrate is added in 30 minutes with a mixture of 25% ammonia (10 ml) and an ammonium chloride saturated solution (10 ml). The mixture is stirred at room temperature for about 3 hours, filtered and the filtered product is washed with water. Upon drying under vacuum, (lib) is obtained (4.4 g, 19.4 moles, 92% yield ) .

Example 5: preparation of 4-( 6-methoxy-2-naphthyl )- butan-2-ol (Ilia)

A mixture of (lib) (1.9 g, 8.4 moles), 10% Pd/C

(0.45 g) dispersed in toluene (10 ml) is stirred under hydrogen atmosphere at 1 atm at room temperature for 1 hour. The mixture is then filtered through Celite, the solvent is distilled off under vacuum and the residue is dried under vacuum to give (Ilia) (1.77 g, 7.72 moles,

92% yield) .

¹H NMR (CDC1₃, delta in ppm): 1.24 (d, 3H); 1.90 (m,

2H); 2.90 (m, 2H ) ; 3.90 (m, 1 H ) ; 3.92 (s, 3H); 7.1-7.4 (m, aromatic, 6H).

Mass-EI m/e (%): 230 (M⁺), 212, 197, 171, 141, 128.

Example 6: preparation of 4-( 6-methoxy-2-naphthyl )- butanone (nabumetone)

A mixture of (Ilia) (0.2 g, 0.87 moles) in acetone (4 ml) is added with calcium hypochlorite (0.09 g, 0.43 moles). The reaction mixture is stirred at room temperature for 24 hours. The mixture is then filtered and the solvent is distilled off under vacuum to give a residue which, upon chromatography on silica gel, yields nabumetone (0.08 g, 0.35 moles, 40% yield). M.p.= 80°C

¹U NMR (DMSO, delta in ppm): 2.09 (s, 3H); 2.84 (m, 4H ) ;

3.83 (s, 3H); 7.1-7.7 (m, aromatic, 6H )

Mass-EI m/e (%): 228 (M⁺), 185, 171, 141, 128.

Example 7 : preparation of nabumetone A solution of (Ilia) (1 g, 4.3 moles) in acetone

(50 ml) kept at reflux temperature is added with a solution of aluminium isopropoxide (0.2 g, 1 mmole) in acetone (50 ml). The reaction mixture is stirred at reflux temperature for 24 hours. The mixture is cooled at 25°C, filtered and the solvent is distilled off under vacuum to give a residue which, after crystallization from ethanol, yields nabumetone (0.7 g, 3.9 moles, 90% yield) . M.p.= 80°C.

¹E NMR (DMSO, delta in ppm): 2.09 (s, 3H); 2.84 (m, 4H);

3.83 (s, 3H); 7.1-7.7 (m, aromatic, 6H). Mass-EI m/e (%): 228 (M⁺), 185, 171, 141, 128. Example 8: preparation of (Ilia)

A mixture of (lib) (40 g, 177 mmoles), 10% Pd/C (2 g) and ethanol (200 ml), is heated to 50÷55°C under stirring. After dissolution, air is removed from the system, washing three times with nitrogen, then the hydrogen gas atmosphere is restored to a total pressure of 3 bars, continuously maintaining such a pressure until ceasing of the absorption. When the reaction is completed (about 3 hours), hydrogen is removed, the system is washed three times with nitrogen, then the air atmosphere is restored; the mixture is cooled at room temperature, added with methanol (300 ml), keeping stirring for about 1 hour. The mixture is filtered through Celite, washing the latter with methanol (150 ml); from mother liquors 450 ml of methanol are distilled off and the residual mass is cooled for 1 hour at 0÷5°C, then filtered. The filtered product is dried under vacuum to give Ilia (24.4 g, 60% yield). Example 9: preparation of (Ilia) A mixture of (lib) (47.5 g, 210 mmoles) and 10% Pd/C (4.8 g) is added with toluene (300 ml) and stirred until dissolution, then air is removed under stirring, the system is washed three times with nitrogen and the atmosphere is restored with gas hydrogen to a total pressure of 3 bars, continuously maintaining such a pressure until ceasing of the absorption. When the reaction is completed (about 9 hours), hydrogen is removed, the system is washed three times with nitrogen, then the air atmosphere is restored; the mixture is filtered through Celite, and mother liquors are evaporated under vacuum to dryness, to give (Ilia) (43.5 g, 90% yield) . Example 10: preparation of (lib) da (la)

A mixture of 6-bromo-2-naphthol (la) (5 g, 22 mmoles), 10% Pd/C (0.47 g), cuprous iodide (0.17 g, 0.88 mmoles), triphenylphosphine (0.3 g, 1.32 mmoles), potassium carbonate (4.6 g, 33 mmoles), dispersed in 5 ml of l-methoxy-2-propanol and 18 ml of water, is kept under nitrogen blanket, stirring for about 30 minutes.

The reaction mixture is added, in about 20 minutes, with 55% aqueous 3-butyn-2-ol (4.2 ml, 32 mmoles), then heated to reflux temperature (90÷95°C) and kept in these conditions for 16 hours; then it is cooled at 25°C, diluted with 50 ml of l-methoxy-2-propanol and filtered through Celite. The evaporation of mother liquors yields (Ila). Mother liquors are added with di ethylsulfate (1.4 g, 11 moles) under stirring; stirring is continued for 30 minutes, then the mixture is added with a 25% ammonia solution (10 ml) saturated with ammonium chloride, in about 30 minutes. The mixture is stirred for about 3 hours, then filtered. The filtered product is dried under vacuum to give lib (2.9 g, 60% yield). 1-H NMR (CDClg) data and mass spectrum are in agreement with those reported above in example 1.

Example 11: preparation of nabumetone

A solution of Ilia (1 g, 4.3 mmoles) in CH₂C1₂ (10 ml) is added, at room temperature, with 8 ml of a solution of K₂Cr₂0 (9.7 g) and concentrated H₂S0₄ (13.6 g) in water (60 ml); the mixture is brought to 40°C keeping this temperature for 4 hours, then extracted three times with 10 ml of toluene, the combined toluene phases are washed first with 10 ml of 0.05 M Na₂S0₃, then with 10 ml of water, dried over MgSO, and finally evaporated to dryness under vacuum to obtain nabumetone (0.6 g, 60% yield) . ¹H NMR (CDC1₃, δ in ppm); 2.15 (s, 3H); 2.85 (m, 2H); 3.05 (m, 2H); 3.92 (s, 3H); 7.1÷7.7 (m, 6H).

Mass-EI m/e (%): 228 (M+), 185, 171, 158, 153, 141. Example 12: preparation of nabumetone

From a suspension of Ilia (1 g, 4.3 mmoles), cyclohexanone (11.5 g, 118 mmoles) and aluminium isopropoxide (0.94 g, 4.6 mmoles) in toluene (54 ml), under reflux, 57.5 ml of mixture are distilled under atmosphere pressure; after that 5 ml of water and 6.2 ml of 10% H₂S0₄ are added, stirring for 15 minutes, then the phases are separated and the aqueous phase is extracted three times with 5 ml of toluene. The combined organic phases are dried over dry MgSO ₄ and evaporated to dryness under vacuum. The resulting crude product is added with absolute ethanol (5 ml), the mixture is refluxed for 30 minutes, then cooled at 0÷5°C keeping this temperature for about 20 minutes. The resulting solid product is filtered and dried under vacuum to give nabumetone (0.6 g, 60% yield).

Example 13: preparation of nabumetone

A mixture of Ilia (1 g, 4.3 mmoles), cyclohexanone (7.7 g, 78.3 mmoles) and aluminium isopropoxide (0.47 g, 2.3 mmoles) is refluxed (154÷156°C), keeping this temperature for 4 hours, then 5 ml of water and 3.1 ml of 10% H₂S0₄ are added. The mixture is stirred for 15 minutes, the phases are separated and the aqueous phase is extracted three times with 5 ml of toluene. The combined organic phases are dried over dry MgS0₄ and evaporated to dryness under vacuum. The resulting crude solid product is added with absolute ethanol (5 ml), the mixture is refluxed for 30 minutes, then cooled at 0÷5°C keeping this temperature for about 20 minutes. The resulting solid product is filtered and dried under vacuum to give nabumetone (0.66 g, 66% yield). Example 14: preparation of nabumetone

A mixture of Ilia (1 g, 4.3 mmoles), cyclohexanone (7.7 g, 78.3 mmoles) and aluminium isopropoxide (0.09 g, 0.4 mmoles) is refluxed (154÷156°C) keeping this temperature for 4 hours, then 5 ml of water and 0.6 ml of 10% H₂S0₄ are added. The mixture is stirred for 15 minutes, the phases are separated and the aqueous phase is extracted three times with 5 ml of toluene. The combined organic phases are dried over dry MgSO, and evaporated under vacuum to dryness. The resulting crude solid product is added with absolute ethanol (5 ml), the mixture is refluxed for 30 minutes, then cooled to 0÷5°C keeping this temperature for about 20 minutes. The resulting solid product is filtered and dried under vacuum to give nabumetone (0.77 g, 77% yield). Example 15: preparation of nabumetone

A mixture of Ilia (1 g, 4.3 mmoles), methyl isobutyl ketone (7.8 g, 78.3 mmoles) and aluminium isopropoxide (0.47 g, 2.3 mmoles) is refluxed ( 116÷118°C) , keeping this temperature for 4 hours; then

5 ml of water and 6.2 ml of 10% H₂S0₄ are added. The mixture is stirred for 15 minutes, the phases are separated and the aqueous phase is extracted three times with 5 ml of toluene. The combined organic phases are dried over dry MgS0₄ and evaporated to dryness under vacuum. The resulting crude solid product is added with absolute ethanol (5 ml), the mixture is refluxed for 30 minutes, then cooled at 0÷5°C keeping this temperature for about 20 minutes. The resulting solid product is filtered and dried under vacuum to give nabumetone (0.59 g, 59% yield). Example 16: preparation of nabumetone

A mixture of Ilia (1 g, 4.3 mmoles), palladium chloride (0.06 g, 0.33 mmoles), cupric chloride dihydrate (0.27 g, 1.6 mmoles) and sodium percarbonate (11.8 g, 43.4 mmoles H₂0₂ ) is suspended in toluene (50 ml) and kept under stirring at room temperature for 22 hours, then added with 20 ml of water. The mixture is stirred for about 15 minutes, the phases are separated, the toluene phase is dried over dry MgS0₄, then evaporated to dryness under vacuum to give nabumetone. Example 17: preparation of 4-( 6-methoxy-2-naphthyl )- buten-2-ol (Illb)

A mixture of 2-bromo-6-methoxynaphthalene (lb) (50 g, 211 moles), 10% Pd/C (4.5 g, 4.2 moles), cuprous iodide (1.6 g, 8.4 moles), triphenylphosphine (2.9 g, 12.7 moles), potassium carbonate (58 g, 422 moles), dispersed in l-methoxy-2-propanol (50 ml) and water (180 ml), is stirred under inert atmosphere (nitrogen) at room temperature for 30 minutes. The mixture is then added in about 20 minutes with 55% aqueous 3-butyn-2-ol

(42 ml, 316 moles) heated to reflux temperature (90-

95 °C) until completion (about 2 hours), cooled at 40-

50°C and diluted with l-methoxy-2-propanol (500 ml). The separated organic phase is hydrogenated under 2 atm at 55°C. At the end of the hydrogenation, the mixture is filtered and the solvent is evaporated off to give compound Illb (97% yield) which, if necessary, is further purified by crystallization from isopropanol. ¹H NMR (CDC1₃, δ in ppm): 1.40 (d, 3H ) ; 3.92 (S, 3H); 4.90 ( , 1H); 5.70 (m, 1H); 6.60 (d, 1H); 7.1-7.7 (m, aromatic, 6H) .

Mass-EI m/e (%) 228 (M+), 210. 195, 185, 171, 158, 152, 139, 128, 115. Example 18: isomerization of compound (Illb) to nabumetone

A mixture of compound (Illb) (2.28 g, 10 mmoles), ruthenium trichloride trihydrate (0.123 g, 0.05 mmoles), potassium carbonate (0.060 g, 0.5 mmoles) and 1-methoxy- 2-propanol (10 ml) is stirred under inert atmosphere (nitrogen) at reflux temperature (120°C) for 4 hours, then cooled at 25°C and filtered through Celite. The solvent is evaporated off under vacuum to give nabumetone (2.18 g, 9.6 mmoles, 96% yield). ¹H NMR (DMSO, δ in ppm): 2.09 (s, 3H ) ; 2.84 (m, 4H ) ; 3.83 (s, 3H); 7.1-7.7 ( , aromatic, 6H).

Mass-EI m/e (%): 228 (M⁺), 185, 171, 141, 128. Example 19: isomerization of (Illb) to nabumetone

A mixture of compound (Illb) (2.28 g, 10 mmoles), ruthenium trichloride trihydrate (0.123 g, 0.5 mmoles), potassium carbonate (0.069 g, 0.5 mmoles) and acetone (10 ml) is stirred under inert atmosphere (nitrogen) at reflux temperature (54-56°C) for 4 hours, cooled at 25°C and filtered through Celite. The solvent is evaporated off under vacuum to give nabumetone (2.16 g, 9.5 mmoles,

95% yield) . Example 20: isomerization of compound (Illb) to nabumetone

A mixture of compound (Illb) (2.28 g, 10 mmoles) ruthenium trichloride trihydrate (0.123 g, 0.5 mmoles), potassium carbonate (0.069 g, 0.5 mmoles) and methyl ethyl ketone (10 ml) is stirred under inert atmosphere (nitrogen) at reflux temperature (80°C) for 4 hours, cooled at 25°C and filtered through Celite. The solvent is evaporated off under vacuum to give nabumetone (2.18 g, 9.6 mmoles, 96% yield). Example 21: isomerization of compound (Illb) to nabumetone

A mixture of compound (Illb) (2.28 g, 10 mmoles), ruthenium dichloride tris-triphenylphosphine (0.096 g, 0.01 mmoles), potassium carbonate (0.069 g, 0.5 mmoles) and tetrahydrofuran (10 ml) is stirred under inert atmosphere (nitrogen) at reflux temperature (64-66°C) for 4 hours, cooled at 25°C and filtered through Celite. The solvent is evaporated off under vacuum and the residue is crystallized from ethanol to give nabumetone (1.82 g, 8 mmoles, 80% yield). M.p. = 80"C.

Claims

1. A process for the preparation of nabumetone, which comprises the following steps: a-L ) alkylation of 6-bromo-2-naphthol (la) with 3-butyn- 2-ol carried out in the simultaneous presence of palladium^⁰) and copper^¹) to give 4-( 6-hydroxy-2- naphthyl )-butyn-2-ol (Ha) and subsequent methylation of compound (Ila) to give 4-( 6-methoxγ- 2-naphthyl )-butyn-2-ol (lib); or, alternatively, a₂ ) alkylation of 2-bromo-6-methoxy-naphthalene (lb) with 3-butyn-2-ol in the simultaneous presence of palladium^⁰) and copper^¹) to give directly (lib); b) total hydrogenation of compound (lib) to give 4- (6- methoxy-2-naphthyl )-butan-2-ol (Ilia) or partial hydrogenation to give 4-( 6-methoxy-2-naphthyl)-3- buten-2-ol (Illb); c) oxidation of compound (Ilia) or isomerization of (Illb) to give nabumetone.

2. A process according to claim 1, wherein Pd(O) used in the step a) is palladium at the oxidation state 0, either at the elementary state or supported with suitable ligands, or in the form of a complex.

3. A process according to claim 2, wherein the ligands are selected from the group consisting of phosphorous ( III ) , nitrogen( III ) or arsenic(III) derivatives .

4. A process according to claim 3, wherein the ligands are selected from the group consisting of triphenylphosphine, triphenylarsine and tetramethylethylenediamine .

5. A process according to claim 2, wherein the palladium complexes are selected from the group consisting of: bis- ( triphenylphosphine )-dichloro complex; bis-( tributylphosphine )-dichloro complex; diallyl- triphenylphosphine-dichloro complex; tetrakis- ( triphenylphosphine ) complex; triphenylphosphine-piperidine-di- chloro complex; bis- ( triphenylphosphine )-diacetate complex; 2, 4-pentanedione complex; 1 , 2-bis- (diphenylpho- sphine )-ethane complex.

6. A process according to claim 1, wherein Cu(I) of step a) stands for copper salts at the oxidation state I, selected from the group consisting of cuprous oxide, cuprous chloride, cuprous bromide, cuprous iodide, cuprous acetate.

7. A process according to claim 1, wherein the reaction of step a) is carried out in the simultaneous presence of Pd/C, a phosphine ligand and a Cu(I) salt, at Pd: ligand :Cu molar ratios ranging from 1:4:2 to 0.5:2:0.5.

8. A process according to claim 1, wherein the palladium molar amounts used in step a) range from 0.01 to 0.05 per mole of 2-bromo-6-methoxynaphthalene .

9. A process according to claim 1, wherein the reaction of step a) is carried out in the presence of a water amount ranging from 1 to 10 volumes per volume of the loaded compound (la) or (lb) and of a protic polar solvent, in particular water-soluble alcohols, in amounts ranging from 1 to 5 volumes per volume of compound (la) or (lb), at a temperature ranging from 20 to 150°C.

10. A process according to claim 1, wherein in step a) the molar ratios of 3-butyn-2-ol to compound (la) or

(lb) range from 1 to 2 equivalents.

11. A process according to claim 1, wherein the reaction of step a) is always carried out in the presence of a base in molar amounts ranging from 1 to 2 equivalents per equivalent of compound (la) or (lb).

12. A process according to claim 11, wherein inorganic bases selected from the group consisting of hydroxides, oxides, carbonates and bicarbonates of alkali metals selected from the group consisting of sodium, potassium, lithium or tertiary organic amine bases selected from the group consisting of triethylamine , diisopropyl- ethylamine, N-methylmorpholine , diazabicyclooctane , are used as the bases.

13. A process according to claim 1, wherein compound (Ila) is transformed into compound (lib) by methylation with methylating agents selected from dimethylsulfate and methyl iodide.

14. A process according to claim 1, wherein total hydrogenation is carried out in the presence of a palladium(0)-on-charcoal catalyst .

15. A process according to claim 14, wherein the molar ratios of palladium(O) to compound (lib) range from 0.01 to 0.1.

16. A process according to claims 14-15, wherein alcohols, aromatic hydrocarbons and esters are used as the solvents in amounts ranging from 1 to 10 volumes per volume of compound (lib).

17. A process according to claims 14-16, wherein the hydrogenation reaction is carried out in the presence of a solvent, under hydrogen atmosphere and a pressure ranging from 1 to 10 atm, and at a temperature ranging from 20 to 120°C.

18. A process according to claim 1, wherein the partial hydrogenation is carried out directly on the organic solution of compound (lib) without its isolation and without addition of further catalyst.

19. A process according to claim 18, wherein the hydrogenation reaction is carried out under hydrogen atmosphere at a pressure ranging from 1 to 10 atm and at a temperature ranging from 20 to 60°C.

20. A process according to claim 1, wherein the oxidation of step c) is carried out using oxidizing agents selected from the group consisting of Mn0₂, KMn0₄, Ni-Raney, DMSO-(COCl )₂ , 0₂/PdCl₂, 0₂ , 0₂/Pt0₂,, peracids, perborates, percarbonates , Br₂, NaC10₄, Cr0₃ (also in form of complexes), Al(OiPr ) ^/acetone.

21. A process according to claim 1, wherein the isomerization of step c) is carried out using catalysts of rhodium(I), palladium( II ) , ruthenium( III ) and ruthenium( II ) .

22. A process according to claim 21, wherein catalysts are used in amounts ranging from 0.005 to 0.1 moles per mole of substrate in the presence of a base in amounts ranging from 0.01 to 0.1 moles per mole of substrate.

23. A process according to claims 21 or 22, wherein solvents selected from alcohols, ketones, ethers or amides are used in amounts ranging from 1 to 5 volumes per volume of substrate.

24. A process according to anyone of claims 22 and 23, characterized in that the temperatures range from 50 to 150°C.