5-[(4-amino-3,5-dimethoxy-phenyl)methyl]pyrimidine-2,4-diamine

Originator

Aditeren ,Onbio Inc.

Manufacturing Process

A solution of 6.9 g of sodium in 1 liter of absolute ethanol were treated with 54 g of guanidine carbonate and 31.0 g of 4-amino-α-(anilinemethylene)-3,5- dimethoxyhyrocinnamic acid nitrile and boiled under reflux for 20 hours. 500 ml of water were added and the alcohol was removed in vacuum. After standing at room temperature for 2 hours, the crystallized 2,4-diamino-5-(4- amino-3,5-dimethoxybenxyl)pyrimidine was filtered off under suction, washed with water and recrystallised from methanol; melting point 215°-216°C.
The starting material was prepared as follows:
13.8 g of sodium were dissolved in 900 ml of methanol. To this solution were added 46.8 g of 3-hydroxy-5-keto-3-cyclohexenecarboxylic acid. This mixture was stirred, held between -4° and -8°C by means of a cooling bath and treated during 30 minutes with a phenyl-diazonium chloride solution [prepared from 27.9 g of aniline, 450 ml of water, 72 ml of concentrated hydrochloric acid and 21.0 g of sodium nitrite in 90 ml of water]. The resulting mixture was stirred for a further 1 hour at -5°C to -10°C. The deposited, red reaction product was filtered off under vacuum and washed with ca 1000 ml of water. There was obtained 3-hydroxy-5-keto-4-phenyl-azo-3-cyclohexenecarboxylic acid of melting point 218°C.
60 g of 3-hydroxy-5-keto-4-phenyl-azo-3-cyclohexenecarboxylic acid, 200 ml of methanol, 1200 ml of benzene and 5 g of p-toluenesulphonic acid were boiled together under reflux on a water separator for 18 hours. After cooling, the solution was washed with 500 ml of a 5% sodium bicarbonate solution, then washed with water, dried and evaporated. The residue was dissolved in ethyl acetate and purified on an aluminum oxide column [500 g; activity stage I]. After evaporation of the ethyl acetate and recrystallisation of the residue from benzene/petroleum ether, there was obtained 3-hydroxIy-5-keto-4- phenyl-azo-3-cyclohexenecarboxylic acid methyl ester as a solid of melting point 144°C.
54.8 g of 3-hydroxy-5-keto-4-phenyl-axe-3-cyclohexenecarboxylic acid methyl ester, 12.0 g of acetamide and 2.0 g of bromosuccinimide were stirred in 600 ml of chloroform and treated dropwise with 32.0 g of bromine in 400 ml of chloroform [the reaction temperature being held below 35°C]. The separation of acetamide hydrobromide soon began. The mixture was stirred for a further 30 minutes at room temperature, the acetamide hydrobromide filtered off and the filtrate evaporated to dryness. The residue was taken up in a small amount of ethanol, filtered off under vacuum and washed with ethanol. There was obtained 3,5-dihydroxy-4-phenylazobenzoic acid methyl ester of melting point 216°-218°C.
A mixture of 27.2 g of 3,5-dihydroxy-4-phenylazobenzoic acid methyl ester, 150 ml of methanol and 64 g of dimethyl sulfate was treated during 45 minutes with a solution of 23 g of sodium hydroxide in 50 ml of water while stirring. Care was taken that the temperature did not exceed 55°C by means of a cooling bath. The mixture was stirred at room temperature for a further 1 hour, cooled with ice water, filtered off under vacuum and recrystallized from 400 ml of ethanol. Red crystals of 3,5-dimethoxy-4-phenylazobenzoic acid methyl ester were obtained; melting point 130°-132°C.
12 g of 3,5-dimethoxy-4-phenylazobenzoic acid methyl ester were dissolved in 400 ml of ethanol and, after the addition of 0.80 g of palladium on carbon, hydrogenated under atmospheric pressure and at room temperature. With slight warming, 2 moles of hydrogen were taken up during 1.5 hours. The catalyst was filtered off and the filtrate concentrated in vacuum. The resulting aniline was distilled off with steam. After cooling, the 4-amino-3,5- dimethoxybenzoic acid methyl ester which remained as an aqueous suspension, was filtered off under vacuum, dried and recrystallised from cyclohexane; melting point 115°-116°C.
A suspension of 214 g of dimethylsulphone and 78.2 g of sodium hydride (50% dispersion in oil) in 400 ml of absolute dimethyl sulfoxide was stirred at 50°C under nitrogen and with exclusion of moisture for 3 hours. The mixture was cooled to 30°C, whereupon 137 g of 4-amino-3,5-dimethoxybenzoic acid methyl ester were added, the temperature rising to 50°C. After stirring under nitrogen and at room temperature for ca 1 hour, the resulting mixture was left to stand for 3 hours and then dissolved in 2 liters of water under addition of ice. The solution was adjusted to pH 6-7 with glacial acetic acid. After stirring under ice-cooling for 1 hour, the crystallized 4'-amino-3',5'-dimethoxy-2- methylsulfonyl-acetophenone was filtered off under suction, washed with water, dried and recrystallised from ethyl acetate; MP: 166°-167°C. A suspension of 123 g of 4'-ammo-3',5'-dimethoxy-2-methylsulphonyl-acetophenone and 68 g of sodium borohydride in 1.5 liters of alcohol was stirred at room temperature for 20 hours. The suspension was diluted with 1.5 liters of water. The alcohol was evaporated in vacuum and the resulting 4- amino-3,5-dimethoxy-α-(methylsulfonylmethyl)benzyl alcohol was filtered off under suction, washed with water and dried; melting point 178°-179°C.
A mixture of 8.64 g of sodium methylate, 14.6 g of p-anilinepropionitrtile and 22.0 g of 4-amino-3,5-dimethoxy-α-(methylsulfonylmethyl)benzyl alcohol in 50 ml of absolute dimethyl sulfoxide was stirred at 50°C for 1 hour under nitrogen and with the exclusion of moisture. The solution was poured into 500 ml of ice-water and the resulting emulsion was extracted with two 500 ml portions of ethyl acetate. The ethyl acetate extracts were washed with two 250 ml portions of water, dried over magnesium sulfate and evaporated in vacuum. The residue was dissolved in 60 ml ethyl acetate. After standing at room temperature for 20 hours, the crystallized 4-amino-α- (anilinemethylene)-3,5-dimethoxyhydrocinnamic acid nitrile was filtered off under suction, washed with a small amount of ethyl acetate and dried; MP: 150°-151°C.

Therapeutic Function

Diuretic