FI109902B - New cardiotonic agent, hypotensive and vasodilator - is optically pure (-)enantiomer of ((4-(1,4,5,6-tetra:hydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazono)propane:di:nitrile - Google Patents

Abstract

(-)-((4-(1,4,5,6-tetrahydro-4-methyl- 6-oxo-3-pyridazinyl)phenyl)hydrazono) propanedinitrile of formula (I) and its pharmaceutically acceptable salts are new. Also new are diastereomeric intermediate solvated salts of formula (III). (I), or its (+)-enantiomer, are made by reaction optically active 6-(4-aminophenyl)-5-methylpyridazin-3-(2H)one (II) with NaNO2 and malononitrile under acid conditions.

Description

109902

METHOD FOR PREPARING PURE ENantiomers of 6- (4-Aminophenyl) -5-methylpyridazin-3 (2H) -one

The present invention relates to a process for the preparation of optically pure (+) and (-) enantiomers of 6- (4-aminophenyl) -5-methylpyrid-5-dazin-3 (2H) -one (II) and to novel intermediates used in the process.

ch3 (+) - h2n-P / = O 11

N-NH

The pure enantiomers of compound (II) are useful as intermediates in the preparation of medicaments useful in the treatment of heart failure.

The racemic 6- (4-aminophenyl) -5-methylpyridazin-3 (2H) one (II) can be prepared by methods known in the literature (J. Med. Chem., 17, 273-281 (1974)). However, the resolution of the racemic compound (II) has proved very difficult because the 4-amino group in the compound is weakly basic. The salts between the 6- (4-15 aminophenyl) -5-methylpyridazin-3 (2H) one and the optically active acids are readily hydrolyzed back to compound (II) and the resolution compound, which interferes with or renders it completely impossible.

European Patent Application EP 208518 describes the separation of the pure enantiomers of compound (20) by a chiral HPLC column.

However, such a method is not applicable on an industrial scale. The enantioselective seven-step synthesis of (-) - 6- (4-aminophenyl) -5-methylpyrrole: ...: dazin-3 (2H) one, starting from (+) - 2-chloropropionic acid ( J. Org. Chem., 56, 1963 (1991)).

The overall yield of this method is only 12% and the optical purity of the (-) - 6- (4-aminophenyl) -5-methylpyridazin-3 (2H) -one obtained is 97.2%.

It has now been found that the enantiomers of compound (II) can be readily resolved using excess L or D-tartaric acid, preferably two to three equivalents, in 2-propanol with compound (II). Acid salt of (-) - 6- (4-amino-phenyl) -5-30 methylpyridazin-3 (2H) -one and 2-propanol solvate of L-tartaric acid. (IIIb) or the corresponding (+) - 6- (4-aminophenyl) -5-methylpyridazin-3 (2H) -one and D-1 · 2 109902 tartaric acid 2-propanol solvate, the acid salt (IIIa) crystallizes in good yield and useful optical purity.

ch3 (+) [H2N- [3-hydroxy-2-propanol solvate] D-tartaric acid]

N-NH

Nv = // N - NH

Further, it has been found that the minor component of the partially enriched enantiomeric mixture can be crystallized out as the racemic compound (II) from dioxane, leaving the major component in solution. Thus, the salts (IIIa) and (IIIb) obtained from the above crystallization process are filtered, the free base is liberated with potassium carbonate solution and the product is treated with dioxane. Both enantiomers of compound (II) can be separated by this biphasic crystallization with high optical purity, greater than 99%. The yield of the process is also very good because the racemic compound (II) is obtained from dioxane in crystalline form and can thus be recycled. Alternatively, both L and D tartaric acid can be used in the above process, but natural L-tartaric acid is less expensive, preferably.

The term "optically substantially pure" herein means an optical purity of greater than 90%, preferably greater than about 95%, and most preferably greater than about 99%.

Example 1 •

Resolution of racemic 6- (4-aminophenyl) -5-methylpyridazin-3 (2H) -one with L - 25 tartaric acid.

v '203 g of (±) -6- (4-aminophenyl) -5-methylpyridazin-3 (2H) -one (1 mol) was dissolved in 2-propanol (40 dm 3) with heating. To this solution was gradually added 300 g (2 moles) of L-tartaric acid. The mixture was stirred with heating until a clear solution was obtained. The solution was slowly cooled to room temperature with stirring. The solution was stirred overnight at 20 ° C and the crystalline product (IIIb) was filtered. The wet salt was dissolved in water (1.5 dm 3) and potassium carbonate solution (190 g '··· * K 2 CO 3 in 0.75 dm 3 water) was added with stirring. The free base was filtered, washed with water and dried. The product (104.6 g) was dissolved in dioxane (0.6 dm 3) with stirring and allowed to cool to room temperature. The racemic 6- (4-aminophenyl) -5-methylpyridazin-3 (2H) one was filtered (74.6 g) and the filtrate evaporated to dryness in vacuo to give (-) - 6- (4-aminophenyl) -5-methyl-5 pyridazin-3 (2H) -one as a crystalline precipitate (23.8 g) with an optical purity of 99.5%, m.p. 207-210 ° C, [.alpha.] D @ 20 = -383 DEG (ethanol-water-conc. HCl 17: 2: 1).

| A solution of 2-propanol containing the (+) enantiomer of compound (II) and the racemate was evaporated to dryness in vacuo. The residue was treated with potassium carbonate stock solution as above to give a mixture of the (+) enantiomer and the racemate 10 (87.3 g) which was dissolved in dioxane (0.48 dm 3) with heating. After cooling, the racemate was filtered (48.0 g) and the filtrate evaporated to dryness in vacuo to give (+) - 6- (4-aminophenyl) -5-methylpyridazin-3 (2H) -one as a crystalline precipitate (26.1 g) being 99.5%, m.p. 206-209 ° C, [.alpha.] D @ 20 = + 391 DEG (ethanol-water-conc. HC117: 2: 1). Total racemate was obtained 15 122.6 g. The (-) enantiomer yield of compound (II) was thus 59.2% and the (+) enantiomer yield 64.9%.

Example 2 Preparation of the pure diastereomeric salt (IIIa) 508 mg (2.5 mmol) of the pure (+) - 6- (4-aminophenyl) -5-methylpyridazin-3 (2H) -one obtained in Example 1 were dissolved in 100 ml of 2-propanol. . 750 mg (5.0 mmol) of D-tartaric acid were added and the mixture was heated to boiling point. On cooling, 800 mg of crystalline (+) - 6- (4-aminophenyl) -5-methyl-: ··· pyridazin-3 (2H) -one D-tartrate mono 2-propanol solvate, m.p. 97-105 ° C.

• · ·

Example 3 • · • ·>: ·. Preparation of the pure diastereomeric salt (IIIb) v: 30 The above process was repeated using (-) - 6- (4-aminophenyl) -5-methylpyridazin-3 (2H) -one and L-tartaric acid. Sp. 98-106 ° C.

t »t 4 109902

Example 4 Preparation of (-) - 6- (4-aminophenyl) -5-methylpyridazin-3 (2H) one by resolution of the corresponding racemate with L-tartaric acid.

203 g (1 mol) of (±) -6- (4-aminophenyl) -5-methylpyridazin-3 (2H) -one were dissolved in 2-propanol (10 dm 3) with heating. To this solution was gradually added L-tartaric acid (300 g, 2 mol). The mixture was stirred while heating until a clear solution was obtained. The mixture was slowly cooled to 50 ° C over 3 hours and stirred overnight at 50 ° C. The crystalline product was filtered and the step described in Example 1 was repeated. The yield of (-) - 6- (4-aminophenyl) -5-methylpyridazin-3 (2H) -one was 30.3 g (97.4% of theory). The optical purity was 99.7%. A total of 140.8 g of racemate was collected.

The optical purity of the compounds was determined by high performance liquid chromatography (HPLC). The apparatus was a Waters 600E gradient pump with a Waters 991 photodiode array detector and a Waters 700 Satellite Wisp injector 15 (Millipore Co.) controlled by an NEC Powermate SX Plus computer. The enantiomers of 6- (4-aminophenyl) -5-methylpyridazin-3 (2H) -one were separated on a cellulose-type chiral column (Chiracel = OJ, 4.6 x 250 mm, Daicel Chemical Industries LTD). The mobile phase consisted of 2-propanol (97%) and hexane (3%). The flow rate was 0.3 ml / min.

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Claims (5)

A process for the preparation of (±) -6- (4-aminophenyl) -5-methylpyridazine-5 (2H) enantiomers, the optical purity of which is above 90%, characterized in that a mixture is obtained of enantiomers to react with an excess of L or D-tartaric acid in 2-propanol, takes the obtained crystalline salt into storage and optionally converts the salt into a free base. Process according to claim 1, characterized in that the free base is further dissolved in dioxane and the filtered solution containing the free optically active base is taken into storage. 3. A process according to claim 1 or 2, characterized in that from about two to three equivalents of L or D tartaric acid is used per one equivalent of enantiomers. 15 4. A process according to any one of claims 1,2 or 3, characterized in that the crystalline salt contains a diastereomeric intermediate salt (purple) or (IIb) ch 3 (+) [h 2 2-propanol soivate] purple N - NH 3 (-) [h2n - \ L = tartaric acid 2-propanol soybate] 11b ·, 20 5. Diastereomeric intermediate salt (purple) or (IIIb) ch 3 '((+) [h 2n-2 y O' D-tartaric acid '2-propanol soybate] Ula (-) [h2n - $ / = L-tartaric acid 2-propanol soybate] H1b