|US pat 3457354 2,4,5-substitutions||Bookmark|
US patent 3457354
Treatment of Hypertension with 2-hydroxy (or amino) –4,5-dihydroxyphenethylamine Derivatives
The solid, the nitrate salt of 2-nitro-4,5-dimethoxy-alpha-methylphenet
The base, 2.72g, was dissolved in absolute alcohol and the solution treated with 3.5mL of a 4.1N solution of dry HCl gas in absolute alcohol. The hydrchloride was recrystallized from a methanol-ether mixture and twice from ethanol-ether mixtures to give product that has; MP: 215.5-216.5*C. Using acid-base procedures and benzene as the non-polar solvent, the base was obtained. The yellow, crystalline freebase has; MP: 81.5-84.5*C.
The product above in the amount of 35.5g (0.148mol) was dissolved in 200ml of absolute alcohol and hydrogenated over Raney nickel at 22*C with an initial H2 pressure of 42 PSI. The catalyst was separated by filtration through a mat of diatomaceous earth. The filtrate was cooled in an ice-bath and a stream of dry HCl passed in until and excess was present. Ether was added and the precipitated solid was collected and recrystallized from a methanol-ether mixture. The hydrochloride of 2-amino-4,5-dimethoxy-alpha-methylphenet
The product of that last step in the amount of 7.92g (0.028mol) was divided into four equal portions. Each was dissolved into 20 ml of conc. HCl acid. These solutions were sealed in glass tubes and heated to 150*C for 2 hours. The tubes were cooled, opened, and the liquid distilled under reduced pressure from a bath at 45-55*C in an atmosphere of N2. After concentrating the solution to near dryness, alcohol was added and the solution crops weighed 5.83g. Recrystallization from mixtures of methanol and ether gave the product, that had; MP: 240-241*C with decomposition.
By using 3,4-dihydroxy-alpha-ethylphenethylamine in place of the alpha-methyl analogure as in Example 1, the title compound of Example 2 was obtained.
2,4,5-trimethoxyphenylacetone (25.0g, 0.111mol), hydroxylamine hydrochloride (9.3g, 0.134mol) and potassium acetate (15.6g, 0.158mol) were added to 400ml of 70% ethyl alcohol contained in a liter flask fitted with a reflux condensor. The mixture was heated on a steam bath to gentle reflux for 3.5 hours. The cooled reaction mixture was evaporated to dryness under vacuum and extracted with benzene 4x150ml. The benzene was washed 2x75ml water then dried with MgSO4. Evaporation of the benzene under reduced pressure left a tan oil (26.8g), which was redissolved in benzene and diluted by dropwise addition of petroleum ether until white crystals appeared. After completion of the crystallization, filtration yielded 20.1g that had; MP: 80-85*C, recryst. w. benzene gave 18.1g of white crystals that had; MP: 91.5-93.0*C
The reaction mixture was filtered to remove the catalyst and the solvent evaporated under reduced pressure to leave a dark yellow residue. The residue was dissolved in excess ether and sufficient 4N alcoholic HCl acid was added to precipitate the hydrochloride of the product. The amine hydrochloride was filtered and washed with ether. It weighed 17.5g and had; MP: 178-181*C. recryst. isopropanol gave; 14.9g of white crystals that had; MP: 186.5-187.2*C
2,4,5-trimethoxybenzaldehyde (30.0g, 0.152mol), n-butylamine (3.2g, 0.044mol), 1-nitropropane (15.7g, 0.176mol) and 50ml of toluene were placed in a 500ml flask fitted with a stirrer, reflux condensor and Dean-stark apparatus. The dark solution was heated for 20 hours while stirring and refluxing. On cooling an orange solid separated and was collected by filtration. The solid yield: 28.6g that had; MP: 97-109*C Upon recrystallization from 300ml of methanol the yield was 22.8g that had; MP: 112-113*C
A solution of 1-(2,4,5-trimethoxyphenyl)-2-nitrobutene
Note: All further examples gave preparations of tablets for administration of the named compounds prepared herein.
US Pat 2858312
Ger Pat 1111642
JOCS (1953) 200-203
Justus Liebigs Annalen der Chemie, 608, 128-139 (1957)
JACS 81, 6236-6240 (1959)
CA v.55, col.20193 ; Subject Index v.55, p18405 (1961)