RESOLUTION OF D,1 2-(6'METHOXY-2'-NAPHTHYL)-PROPIONIC ACID

Abstract: Process for separating d 2-(6′-methoxy-2′-naphthyl)-­ propionic acid, commonly known as Naproxen, by frac­ tioned crystallization in water of a mixture of the corre­ sponding disteroisomer salts obtained by treatment of the d,l 2-(6′-methoxy-2′-naphthyl)-propionic acid with (-)-­ alpha-phenylethylamine in water.

Description: RESOLUTION OF DL 2-(6'-METHOXY-2'-NAPHTHYL)-PROPIONIC ACID The present invention relates to a new process for preparing the d 2-(6'-methoxy-2'-naphthyl)-propionic acid, commonly known as Naproxen, by fractioned crystal lization in water of a mixture of the corresponding diasteroisomer salts obtained by treatment of a mixture of the d,l 2-(6'-methoxy-2'-naphthyl)-propionic acid with (-) alpha-phenylethylamine, separation of the precipitate and subsequent treatment of the precipita te itself wit acids, characterized in that the whole process is carried out in water. The Japanese Patent Application published under the No. 55/055136 discloses a process for preparing Naproxen by resolving a mixture of d,l 2-(6'-methoxy 2' naphthyb--propionic acid acid by using (-)-alpha-phenyl ethylamine in an organic solvent. It has now been found that both the salification of d,l-Naproxen with (-)-alpha-phenylethylamine and the subsequent separation of the thus obtained disteroiso mers by fractioned crystallization, can be carried out in water. The amount of (-)-alpha-phenylethylamine used ranges from 1 to 0.1 mols for each mol of d,l 2-(6'-methoxy 2'-naphthyl)-propionic acid. When it is used less than I mol of (-)-alpha-phenylethyl amine the salification of d,1 2-(6'-methoxy-2'- naphthyl)- propionic acid is completed by adding an organic or inorganic base su:h as an alkylamine, an alkaline hydroxide ,ammonium hydroxide, etc. The salt of (-)-alpha-phenylethylamine and Naproxen which precipitates s separated from the reaction mixture by fil tration at a temperature comprised between 0 C and 1000C. The thus obtained product is treated with acids; the product which precipitates shows a rotatory power compri sed between 100 and 660. When the optical purity of the precipitated product is not high enough the repetition of the above specified operation or Subsequent crv- stallization from water allow to obtain the product having the desired purity. The yields of each crystallization vary, according to the operation conditions, from 5 to 90%. The yields ofthis process can be conveniently impro ved by adding salts such as alkaline or ammonium salts of carboxylic aliphatic acids. The following examples should not be considered as a limitation upon the scope of the invention but mere ly as being illustrati-ve and representative thereof. EXAMPLE 1 (-)-alpha-phenylethylamine (60 g, 0.5 mols) is added in 5', under stirring, to a suspension of di-Naproxen (115 g, 0.5 mols) in water (2 l) warmed at 40 C. The mixture is heated at reflux under stirring for 30', then it is cooled in 1 hour and 15' at OOC. The solid residue is separated by filtration, washed with hot water (OOC) and suspended in diluted hydrochloric acid; the insoluble is filtered, washed with water and dried. A mixture of the two enantiomers of the 2-(6'-metho xy-2' -aphthyl)-propionic acid having |&alpha;|D20 + 49.6 is thus obtained. EXAMPLE 2 A mixture of (-)-alpha-phenylethylamine (15.1 g; 0.125 mols) and of triethylamine (12.63 g; 0.125 mols) is added in 5', under stirring, to a suspension of d,l -2-(6'-methoxy-2' -naphthyl) -propionic acid (57.5 g; 0.25 mols) in water (1 1), heated at 600C. The mixture is kept under stirring, at 600C for 20 hours. The solid residue is separated by filtration, washed with hot water (600C; 250 ml) and dried attheair; a mixture of the diasteroismer salts (28 g) is thus obtained. An aliquotis suspended in diluted hydrochloric acid, the in soluble is filtered, washed with water and dried at the air. An acid having |&alpha;|D20 + 50 is thus obtained. In a parallel test the wet salt is suspended in water (500 ml); the mixture is kept at 600C for 15 hours and then brought to 90 C and kept at this temperature for 3 hours. It is then cooled to 600C in 3 hours and kept at this temperattlre for 10 hours. The solid residue is separated by filtration, washed with hot water (600C) and suspended in diluted hydrochloric acid; the insoluble is filtered, washed with water and dried at the air. An acid having |&alpha;|D20 + 60 is thus obtained. In a second parallel test carried out in similar con ditions, a 10 molar solution of triethylamine acetate (1.58 ml) has been added to the salt suspension in water; 20 an acid having |&alpha;|D20 62 has been thus obtained. Similar results have been obtained using NH OH, KOH 4 and NaOH instead of triethylamine. XAMPLE (-)-alpha-phenylethylamine (15.1 g; 0.125 mols) and triethylamine (12.63 g; 0.125 mols) are added under stirr ing to a suspension of d,l-2-(6'-methoxy-2'-naphthyl)propionic acid (57.5 g; 0.25 mols) in water (1 1) heat ed at 1000C. The mixture is refluxed for 1 hour and then is cool ed slowly (100C per hour) to 250C and kept at 250C for 12-14 hours. The solid residue is recovered by filtrat ion and washed with cool water. After drying it is obtained a mixture of the diasteroisomer salts (36 g). An aliquot (4 g) is hydrolized with hydrochloric acid to give a product having |&alpha;|D20 + 46.87 . EXAMPLE 4 The procedure of Example 3 is repeated by using a 32% of acqueous solution of ammonia (7.5 ml; 0.125 ml) instead of triethylamine. Yield, 35.4 g. An aliquot of the thus obtained diastomer salts is hydrolized to give a product having 20 + + 47.220. Another aliquot (10 g) is suspended in water (150 ml) and refluxed for I hour; the mixture is then cooled slow ly. The thus obtained mixture of diasteroisomer salts (7.9 g) is then hydrolized to give a product having |&alpha;|D20 + 60.1. All the above mentioned rotatory powers have been ob tained in chloroform (C=0,01)

Claims: CLAIMS 1. Process for preparing d 2-(6'-methoxy-2'-naphthyl) -proT?ioflic acid hv fractioned crystallization of a mixture of the diasteroisomer salts obtained by treat ment of the d 2-(6'-methoxy-2'-naphthyl)propionic acid with (-)-alpha phenylethylamine, separation of the precipitate and subsequent treatment of the pro duct with acids characterized in that the whole pro cess is carried out in water. 2. Process according to claim 1, characterized in that from 0.1 to 1 molsof (-)-alpha-phenylethylamine are used for each mol of d,l 2-(6'-methoxy-2'-napilthyl)- propionic acid. 3. Process according to claim 2, characterized in that when less than one mol of (-)-phenylethylamine is used the formation of the salt of the d,l 2-(6'-me thoxy-2'ilaphthy1)-propionic acid is completed by ad ding an organic or inorganic base. 4. Process according to claim 1, characterized in that the precipitation of the salt of the d 2-(6'-methoxy -2'-naphthyi)-propionic acid and (-)-phenylethylamine is favoured by adding a salt.

Inventors: CASTALDI, GRAZIANO, GIORDANO, CLAUDIO, UGGERI, FULVIO, VILLA, GIOVANNI
Applicants: BLASCHIM S.P.A.
Application year: 1982
Main classification: C07B57
IPC codes: C07C59, C07C67, C07C51