NL8900721A - PROCESS FOR THE PREPARATION OF 4- (6'-METHOXYNAFTYL-2 ') - BUTENON-2. - Google Patents

Description

- i -

Process for the preparation of 4- (6-methoxyphenyl-2t) -butenone-2.

This invention relates to a new process for preparing an intermediate useful in the preparation of 4- (6'-methoxynaphthyl-2 ') butanone-2.

U.S. Patent 4,420,639 describes 5- (6'-methoxynaphthyl-2 ') butanone-2 (nabumetone) and its use for the treatment of rheumatics and arthritis. A number of methods for preparing that compound have also been described, one of which proceeds through the unsaturated compound of Formula I.

A process for preparing the compound of formula I has now been found which is characterized by a palladium-catalyzed addition of methyl vinyl ketone to 2-methoxynaphthalene, a 2-halo-6-methoxynaphthalene or a 6-methoxy-2-naphthoyl chloride.

Accordingly, this invention provides a process for the preparation of 4- (6'-methoxynaphthyl-2 ') -3-butenone-2, characterized in that a compound according to formula II, wherein X is hydrogen, halogen or a group CO2Cl , in the presence of a palladium catalyst, reacts with methyl vinyl ketone of formula III.

The term "halogen" here includes iodine, bromine and chlorine, and preferably bromine. The palladium catalyst can be palladium itself or a palladium (II) compound. Suitable palladium (II) compounds include palladium (II) acetate, a palladium (II) triphenylphosphine complex and palladium (II) halides such as palladium (II) chloride, bromide and iodide.

When palladium is used as a catalyst, a preferred physical form thereof is palladium on charcoal, such as 5% palladium on charcoal.

When X in formula II is hydrogen, the reaction preferably occurs at an elevated temperature such as between 50 ° and 150 ° C, preferably about 80 ° G to 120 ° C, and most preferably for 1 to 10 hours. The reaction is preferably conducted in an inert solvent, and glacial acetic acid is particularly preferred.

8900721 ί "2 -

When X in formula IX is the group -COCl, the reaction preferably takes place at a temperature between 100 ° and 150 ° C for one to five hours, under nitrogen and in the presence of a base such as a tertiary amine in an inert solvent. Suitable inert solvents are xylene and toluene, and a suitable amine is N-benzyldimethylamine. An advantage of this reaction is that xylene and toluene are inexpensive and easy to recover and that the tertiary amine is also easy to recover.

When X in formula II is halogen, the reaction preferably takes place at a temperature between 100 ° and 150 ° C for 1 and 12 hours and under nitrogen. A suitable reaction medium is a mixture of sodium carbonate and dimethylformamide.

It has proved advantageous to generate the methyl vinyl ketone in Situ by dehydrohalogenation of a 4-halobutanone, in particular of 4-chlorobutanone. Such dehydrohalogenation can be carried out by reacting the 4-halobutanone with sodium carbonate in dimethylformamide. Advantageous yields of the compound of formula I can be achieved by slowly adding the 4-halobutanone to the reaction mixture over several hours in the presence of dimethylformamide and sodium carbonate.

Another in situ preparation of the methyl vinyl ketone consists of the pyrrolysis of 4-diethylaminobutanone-2, preferably at a temperature of about 130 ° C and preferably in the presence of dimethylformamide and sodium carbonate.

The in situ preparation of methyl vinyl ketone is particularly suitable in the process of the invention when X in formula II is halogen.

Although stoichiometric amounts of the reactants and the catalyst can be used in the process of the invention, it has been found that when X in formula II is hydrogen, the yield of the compound of formula I can be increased by a molar excess of both catalysts Sator to be used as methyl vinyl ketone. Preferably an excess of 50% or more of both catalyst and ketone is used.

Alternatively, the amount of catalyst can be reduced by also adding an oxidizing agent to the reaction mixture.

- 3 - Take ς to oxidize the deposited palladium metal again. A suitable means for this is an intermediate catalyst such as copper (II) or silver (I) acetate in the presence of oxygen. The amount of catalyst thus reduced can nevertheless give a sufficient yield of end product, while the catalyst costs are kept to a minimum.

Compounds of formula II wherein X is halogen are known compounds and are prepared by methods analogous to those for preparing structurally related known compounds.

The compound of formula II wherein X is hydrogen (2-methoxynaphthalene) is also a known compound, while the compound wherein X is the group -COCl can be prepared from standard 2-acetyl-6-methoxynaphthalene (itself a known compound) (See GW Gray and B. Jones in J. Chem. Soc. 678 (1954) and R. Gay and A. Horeau in Bull. Soc. Chim. France, 622 (1953). The 4-chlorobutanone can be prepared by a Friedel-Crafts reaction of ethylene with acetyl chloride in the presence of aluminum chloride, or by chlorination of 4-hydroxybutanone.

20, The invention is illustrated by the following examples.

Example 1

A mixture of 0.47 g (3.0 mmol) 2-methoxynaphthalene, 0.32 g (4.5 mmol) methyl vinyl ketone, 1.0 g (4.5 mmol) palladium acetate and 7 ml glacial acetic acid was added for 3 hours stirred at 105-110 ° C under nitrogen. Samples were taken from the reaction mixture and examined by HPLC (for the conditions see below) and that assay was quantitated with the desired 3-butenone-2 as a calibration substance.

30 HPLC conditions

Elutants: 60% aetonitrile / 40% water Column: Spherisorb 0DS2

Running speed: 1 ml / min

Wavelength: 310 nm. The chromatogram showed a yield of 3-butenone-2 of about 25%.

Example 2

A mixture of 4.7 g (30 mmol) of 2-methoxynaphthalene, 3.2 g (45 mmol) of methyl vinyl ketone, 0.91 g (4.0 mmol) of palladium- 8900721 * f - 4 -acetate, 0.9 g ( 4.5 mmol) cupric acetate monohydrate and 50 ml of ice vinegar were stirred at 105-110 ° C for 8 hours. Air was passed through the mixture during the reaction. Samples were taken and examined by HPLC. These showed a gradual increase in the amount of 3-butenone-2 formed from 2.6% to 12.6%.

Example 3

A mixture of 4.4 g (20 mmol) 6-methoxy-2-naphthoyl chloride, 45 mg (0.2 mmol) palladium acetate, 1.75 g (25 fflmol) methyl vinyl ketone and 3.38 g (25 mmol) N Benzyl dimethylamine in 40 ml of 10 p-xylene was heated to 130 ° C under nitrogen for 4 hours. The reaction mixture was cooled and the precipitate of N-benzyldimethylammonium chloride was filtered off and washed with 10 ml of p-xylene. The combination of filtrate and washings was then washed with 2 x 15 ml 2N hydrochloric acid, 20 ml saturated NaHCO 2 solution and 20 ml water. The p-xylene solution was dried over MgSO4, filtered and evaporated to 3.7 g of yellow-brown semi-solid (82% yield). Research by HPLC showed that the desired naphthoylbutenone was 48.3%, which, based on the naphthoyl chloride, represented a yield of 39.6%.

20 Example 4

A mixture of 5.9 g (25 mmol) of 2-bromo-6-methoxy-naphthalene, 2.45 g (35 mmol) of methyl vinyl ketone, 0.27 g of 50% paste of 5% Pd / C (0.065 mmol), 1 59 g (15 mmol) sodium carbonate and 60 ml dimethylformamide were heated to 130 ° C under nitrogen for 6 hours. The reaction mixture was cooled to 20 ° C and the catalyst was filtered off. The filtrate was poured into 250 ml of water and the resulting suspension was stirred for 15 minutes. The product was filtered off, washed with 2 x 40 ml water and dried under vacuum at 45 ° C for 16 hours to give 5.4 g of a pale beige solid containing 43.8% of the desired 3-butenone-2, a yield of 42%.

Example 5

A mixture of 2.37 g (10 mmol) 2-bromo-6-methoxy-naphthalene, 2 g (20 mmol) methyl vinyl ketone, 90 mg (0.9 mmol) triethylamine, 1.0 g (12 mmol) sodium bicarbonate .70 mg (0.1 mmol) 35 bis (triphenylphosphine) palladium (II) chloride, 2 ml p-xylene and 5 ml water were added 3 | heated to 100 ° C under stirring. After cooling to room temperature, 15 ml of toluene and 5 ml of water were added and the mixture was stirred for an additional 10 minutes. The water phase was separated from the organic phase and washed with 5 ml of toluene. The com-S900721.

Combination of filtrate and washings was washed with 5 ml, dried over MgSO 4 and filtered to remove the desiccant. The toluene solution was now evaporated to dryness under vacuum to give 4.4 g of a yellow-orange, semi-solid product. This was found to be 32.3% of the desired 6-methoxynaphthylbutenone, a yield of 62.9 Z.

Example 6

A mixture of 4.7 g (20 mmol) 2-bromo-6-methoxy-naphthalene, 1.75 g (25 mmol) methyl vinyl ketone, 2.53 g (25 mmol) triethylamine, 164 mg (1.6 mmol) triphenylphosphine and 45 mg (0.2 10 mmol) of palladium acetate was heated to 100 ° C in a sealed tube under nitrogen for 20 hours. The solid contents tube was cooled to room temperature and the contents were dissolved in 50 ml of toluene with stirring. That solution was filtered to remove precipitated triethylammonium bromide and the filter cake was washed with 10 ml of toluene. The combination of filtrate and washing liquid was evaporated to dryness to give 4.87 g of a yellow-brown semi-solid product. This was found to be 60% the desired methoxynaphthylbutenone, representing a yield of 64.6%.

Example 7 In a stirred mixture of 5.9 g (25 mmol) 2-bromo-6-methoxynaphthalene, 0.27 g 50% paste of 5% Pd / C (0.065 mmol), 3.82 g (36 mmol) sodium carbonate and 60 ml of dimethylformamide were added dropwise with stirring and under nitrogen at 130 ° C over 1 hour a solution of 3.72 g (35 mmol) of 4-chlorobutanone in 5 ml of dimethylformamide. The reaction mixture was heated at 130 ° C for an additional 2 hours and then cooled to room temperature. The catalyst was filtered off and the filtrate poured into 250 ml of water with stirring. After 15 minutes, the product was filtered off, washed with 2 x 40 ml of water and dried under vacuum at 45 ° C for 16 hours; this gave 5.0 g of off-white fabric. This was found to be the desired naphthyl butanone for 75.6 L, a yield of 67.2%.

Example 8

In a stirred mixture of 5.9 g (25 mmol) 2-bromo-6-methoxynaphthalene, 0.27 g 50% paste of 5% Pd / C (0.065 mmol), 35 1.55 g (14.6 mmol) sodium carbonate and 50 ml dimethylformamide were dripped over 3 hours under nitrogen and at 130 ° C a solution of 3.2 g (22 mmol) 4-diethylaminobutanone in 10 ml dimethylformamide. The reaction was followed by HPLC and after 10 hours at 130 ° C a yield of 58% of desired naphthylbutenone was determined.

8900721 ...

Claims (9)

Process for the preparation of 4- (6'-methoxy-naphthyl-2 ') -3-butenone-2, characterized in that a compound 5 according to formula II, in which X is hydrogen, halogen or a group -COCl, react with methyl vinyl ketone of the formula III in the presence of a palladium catalyst. The method of claim 1, wherein the palladium catalyst is palladium itself or a palladium (II) compound. The method of claim 2, wherein the palladium (II) compound is palladium (II) acetate, a palladium (II) halide or a palladium (II) triphenylphosphine complex. A method according to any preceding claim, wherein X is hydrogen, bromine or iodine. The process according to any of the preceding claims, wherein X is halogen and the reaction is carried out in the presence of sodium carbonate. 6. A method according to any one of the preceding claims, wherein the methyl vinyl ketone is formed in situ in the reaction mixture. The method of claim 6, wherein the methyl vinyl ketone is formed by dehydrohalogenation of a 4-halobutanone or by pyrolysis of 4-diethylaminobutanone-2. 8. Process for preparing 4- (6'-methoxy-naphthyl-2?) - 3-'-butenone-2, characterized in that a compound of formula II, as defined in claim 1, wherein X is hydrogen , react with methyl vinyl ketone in the presence of palladium acetate and acetic acid. 9. Process for preparing 4- (6'-methoxy-naphthyl-2 ') -3-butenone-2, characterized in that a compound of formula II, as defined in claim 1, wherein X is halogen, is presence of palladium-on-carbon, sodium carbonate and dimethylformamide with 4-chlorobutanone. 35 -o-o-o-o-o- 89 00 711 r.