Aurelius (Hive Addict) 01-21-03 04:00 No 400055				US pat 3457354 2,4,5-substitutions	Bookmark
						US patent 3457354 Treatment of Hypertension with 2-hydroxy (or amino) –4,5-dihydroxyphenethylamine Derivatives Example 1: 2-amino-4,5-dihydroxy-alpha-methylphenethylamine dihydrochloride 2-nitro-4,5-dimethoxy-alpha-methylphenethylamine 3,4-dimethoxy-alpha-methylphenethylamine (4.0g, 0.0205mol) was added dropwise to a mixture of 32ml of conc. HNO3 (d= 1.4) and 12mL of H2, while stirring and maintaining the temperature of 12-15*C. by external cooling.  When the addition was complete, the solution was stirred at 10-15*C for 3 hours.  After standing an additional 30 minutes at this temperature, it was cooled to 0*C.  and poured into 50mL of an ice-water mixture.  The pale yellow solid that separated was collected and air dried. The solid, the nitrate salt of 2-nitro-4,5-dimethoxy-alpha-methylphenethylamine was suspended in water, the mixture rendered alkaline with sodium carbonate, and the base extracted into chloroform.  After washing with water, the chloroform extract was dried over sodium sulfate and the solvent distilled under reduced pressure.  The brown oily residue solidified on cooling.  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. 2-amino-4,5-dimethoxy-alpha-methylphenethylamine dihydrochloride 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-methylphenethylamine was obtained as a tan crystalline solid that has; MP: dependent on rate of heating.  2-amino-4,5-dihydroxy-alpha-methylphenethylamine dihydrochloride 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. Example 2: 2-amino-4,5-dihydroxy-alpha-ethylphenethylamine dihydrochloride 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. Example 3: 2,4,5-trihydroxy-alpha-methylphenethylamine 1-(2,4,5-trimethoxyphenyl)-2-oximinopropane 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 1-(2,4,5-trimethoxyphenyl)-2-aminopropane 1-(2,4,5-trimethoxyphenyl)-2-oximinopropane (18.1g, 0.075mol) was dissolved in 200ml of methyl alcohol and subjected to hydrogenation in the presence of one teaspoon of Raney nickel at 100*C and 1700psi.  Observed pressure drop at 20*C was 100psi. 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-trihydroxy-alpha-methylphenethylamine hydrobromide 2,4,5-trimethoxy-alpha-methylphenethylamine hydrochloride (3.0g, 0.0115mol), 65ml of bromine free 48% HBr acid and 65ml of glacial acetic acid were mixed under N2 and refluxed for 16 hours in the same atmosphere.  The solvent was removed under reduced pressure and hot water bath.  Methano containing SO2 was added to the residue and removed under reduced pressure.  The latter process was repeated and the ersidue dissolved in 50ml of water containing SO2.  The solution was treated with acid washed “Norit” and filtered through and an acid washed “Norit” pad on a porcelain filter while protecting it from oxygen with a N2 atmosphere.  The filtrate was evaporated to dryness under reduced pressure and hot water bath to leave a glassy residue.  This material was treated with ethyl alcohol containing SO2 4 times and the solvent removed under pressure each time.  Repeated attempts to obtain a crystalline material from butanol/ether mixtures were unsuccessful.  The glassy hydrobromide crystallized after several months under N2 atmosphere in refrigeration. Example 4: 2,4,5-trihydroxy-alpha-ethylphenethylamine hydrobromide 1-(2,4,5-trimethoxyphenyl)-2-nitrobutene-1 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 2,4,5-trimethoxy-alpha-ethylphenethylamine hydrochloride A solution of 1-(2,4,5-trimethoxyphenyl)-2-nitrobutene-1 (26.7g, 0.1mol) dissolved in 250ml of dry THF was added dropwise to a stirring, refluxing solution of LAlH4 (18.0g) in two liters of reagent grade ether over a period of 1.5 hours.  The mixture was refluxed with stirring and calcium chloride tube protection for an additional 2-3 hours and the excess LAlH4 decomposed by the dropwise addition of ethyl alcohol.  Sodium potassium tartrate solution (600ml @ 40%) and 250ml of water were added.  The mixture was transferred to a large separatory funnel and the ether phase separated.  The aqueous phase was extracted 3x50ml of ether and the ether phases were all combined.  The ether was dried over potassium hydroxide.  Evaporation of the ether under reduced pressure left a white oily solid which was dissolved in alcohol, treated with charcoal and filtered.  The clarified alcohol solution was treated with 30ml of 5.8N alcoholic HCl acid and the solution diluted with ether and chilled to give white crystals of yield 16.0g that had; MP: 206-207*C 2,4,5-trimethoxy-alpha-ethylphenethylamine hydrochloride 2,4,5-trimethoxy-alpha-ethylphenethylamine hydrochloride (5.52g, 0.02mol), 100ml of Br2 free 48% HBr acid were treated by the same procedure as described for the alpha-methyl analogue and a clear amber glassy product was obtained which did not crystallize. Note: All further examples gave preparations of tablets for administration of the named compounds prepared herein. References Cited: 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)