WO2001049660A1

WO2001049660A1 - A process for preparing 3-{[3-chloro-4-(methylsulfonyl)-phenyl]methylene}-2,4-pentanedione

Info

Publication number: WO2001049660A1
Application number: PCT/FI2000/001150
Authority: WO
Inventors: Kari Lönnberg; Reijo Bäckström
Original assignee: Orion Oyj
Current assignee: Orion Oyj
Priority date: 1999-12-30
Filing date: 2000-12-28
Publication date: 2001-07-12
Anticipated expiration: 2002-06-30
Also published as: GB2373249B; GB2373249A; GB0215787D0; AU2519601A

Abstract

3-{[3-Chloro-4-(methylsulfonyl)phenyl]methylene}-2,4-pentanedione is prepared from 3-chloro-4-(methylsulfonyl)benzaldehyde and 2,4-pentanedione using 2-propanol or 2-propanol and DMF as a solvent and an amine optionally with a weak acid as a catalyst.

Description

A PROCESS FOR PREPARING 3-{[3-CHLORO-4-(METHYLSULFONYL)- PHENYL]METHYLENE}-2,4-PENTANEDIONE

The present invention relates to a process for preparing a new molecule, 3-{ [3-chloro- 4-(methylsulfonyl)phenyl]methylene} -2,4-pentanedione, having a structure (I)

using 2-propanol or a mixture of 2-propanol and dimethylformamide (DMF) as a solvent and an amine or amine and a weak acid as a catalyst. 3-{ [3-Chloro-4- (methylsulfonyl)phenyl]methylene} -2,4-pentanedione is found to be suitable for the prevention and treatment of respiratory diseases, especially asthma.

Patent application EP 0 440 324 describes substituted diketones and their use. The preparation of several molecules with analogous structures to (I) has been described. Eg. toluene, tetrahydrofurane, trifluoroacetic acid and 2-propanol have been mentioned as suitable solvents in the processes. In addition there are used eg. piperidine and acetic acid or thionyl chloride as catalysts. Eg. 3-[(4- methylsulfonylphenyl)methylene]-2,4-pentanedione has been prepared in 2-propanol using thionyl chloride as a catalyst. The solution is evaporated to dryness in vacuo and the product is crystallized from toluene. In another example 3- [(3, 4- dichlorophenyl)methylene]-2,4-pentanedione is prepared using toluene as a solvent and piperidine and acetic acid as catalyst. Anyhow, none of the examples describe 3- { [3-chloro-4-(methylsulfonyl)phenyl]methylene} -2,4-pentanedione, nor the use of 2- propanol as a solvent with an amine as a catalyst in the preparation of similar compounds.

Accordingly, the object of this invention is the preparation of 3-{ [3-chloro-4- (methylsulfonyl)phenyl]methylene} -2,4-pentanedione from 3-chloro-4- (methylsulfonyl)benzaldehyde (II)

and 2,4-pentanedione (III)

using 2-propanol or 2-propanol and DMF as a solvent and amine or an amine and a weak acid as a catalyst. The product is recovered from the reaction mixture with high yield and purity without need of separate crystallization step.

3-Chloro-4-(methylsulfonyl)benzaldehyde (II) can be prepared eg. from halogenated benzaldehydes, eg. 3-chloro-4-fluorobenzaldehyde or 3,4-dichlorobenzaldehyde and sodium salt of methanesulfinic acid, eg. from 3,4-dichlorobenzaldehyde and methanesulfinic sodium salt as described in example 1.

When compound (I) is prepared by the process according to the invention, compound (II) is allowed to react with compound (III) in 2-propanol or in the mixture of 2- propanol and DMF in the presence of an amine, preferably a secondary amine and most preferably piperidine or in the presence of amine and a weak acid, preferably organic acid and most preferably acetic acid or formic acid. The acid is used in proportion to amine from 0 to 4 equivalence, preferably in proportion 1 : 1. 2,4- Pentanedione (compound III) is used from 1 to 5 equivalents to 3-chloro-4- (methylsulfonyl)benzaldehyde (compound II), preferably 2 to 3 equivalents. If the mixture of 2-propanol and DMF is used, 2-propanol is used 2,5 - 4,5 times the amount of DMF, preferably the ratio of DMF to 2-propanol is from 1:3 to 1 :4, most preferably 1 :3,5.

3,4-Pentanedione is added to a mixture containing 3-chloro-4-(methylsulfonyl)- benzaldehyde, amine and optionally an acid in 2-propanol or in 2-propanol and DMF. The mixture is stirred in ambient temperature overnight. The product is separated by filtration and washed with cold 2-propanol.

Alternatively the suspension of 3-chloro-4-(methylsulfonyl)benzaldehyde in 2- propanol is first warmed to about 50 - 70 °C, cooled to ambient temperature, and thereafter 2,4-pentanedione, amine and optionally an acid are added. The solution is mixed overnight. The product is separated by filtration and washed with cold 2- propanol.

It is also possible to perform the reaction in higher temperature, about 50 - 70 °C , and use a shorter reaction time, from 1 to 10 hours. After the reaction is complete, the mixture is cooled to and the product is filtered and washed.

The following example will illustrate the invention:

Example

3-chloro-4-(methylsulfonyl)benzaldehyde

To a solution containing 1.0 g of 3,4-dichlorobenzaldehyde in 45 ml of DMSO was added 1.93 g of methanesulfinic acid sodium salt with stirring at 90 °C . The solution was stirred for 6 hours at 90 °C and then poured in water. Sodium hydrogen carbonate was added to adjust the pH to about 8 and the product was extracted with ethyl acetate. The extract was evaporated to dryness in vacuo. The residue was triturated with 2-propanol, yield 1.06 g. 3- { [3-chloro-4-(methylsulfonyl)phenyl]methylene } -2,4-pentanedione

To a solution containing 2.5 g of 3-chloro-4-(methylsulfonyl)benzaldehyde, 0.13 ml of piperidine and 0.05 ml of formic acid in 70 ml of 2-propanol was added 2.6 ml of 2,4-pentanedione with stirring at 20 °C . The solution was stirred overnight at 20 °C. The product was filtrated and washed with 2-propanol, yield 2.1 g (60 %), mp. 140- 142 °C. 1H-NMR (DMSO-d₆ ,400 MHz): 2.28 (s, 3H, CH₃), 2.50 (s, 3H, CH₃), 3.40 (s, 3H, CH₃), 7.59 (dd, J=8.2Hz, 1.6Hz, 1H, ArH), 7.78 (s, 1H, CH), 7.80 (d, J=1.6Hz, 1H, ArH), 8.09 (d, J=8.2Hz, 1H, ArH).

Claims

1. A process for preparing 3- { [3-chloro-4-(methylsulfonyl)phenyl]methylene} -2,4- pentanedione from 3-chloro-4-(methylsulfonyl)benzaldehyde and 2,4- pentanedione characterized in th at the process is performed in 2-propanol and an amine is used as a catalyst.

2. A process according to claim 1 wherein dimethylformamide is added to the solvent.

3. A process according to claims 1 or 2, characterized in that the amine used is a secondary amine.

4. A process according to claim 3 characterized in that the secondary amine is piperidine.

5. A process according to any of claims 1 to 4, characterized in that weak acid is used as an additional catalyst.

6. A process according to claim 5, characterized in that the weak acid used as an additional catalyst is an organic acid.

7. A process according to claim 6, characterized in that the organic acid used is formic acid or acetic acid.

8. A process according to any one of claims 5 to 7, characterized in th at the molar ratio of amine to acid is from 0 to 1 :4.

9. A process according to claim 5 to 8, ch aracterized i n that the molar ratio of amine to acid is 1: 1.