GB Patent 1036290
A Process for the Manfacture of Phenyl-Amino-Propane Derivatives
Abstract:
The process provided by the present invention, which is a technically simple process and enables the xylopropamine to be obtained in a pure form (that is to say, free from undesired isomers), comprises diazotizing 1-amino-3,4-dimethylbenzene, reacting the diazonium product with formaldoxime, hydrolyzing the resulting 3,4-dimethylbenzaldoxime, condensing the 3,4-dimethylbenzaldehyde obtained with nitroethane, reducing the resulting 3,4-beta-trimethyl-beta-nitrostyrene and, if desired, converting the resulting 1-(3,4-dimethylphenyl)-2-aminopropane into an acid addition salt.
Example 1:
A mixture of 46g of paraformaldehyde, 105g of hydroxylamine hydrochloride and 680ml of water heated on the steam-bath in a 2L RB flask until complete solution had occurred. 204g of sodium acetate were then added and the solution obtained was boiled under reflux on an oil-bath for 15-20minutes. The solution was then cooled to 10*C and decanted into a 6L flask which was fitted with a stirring device, a reflux condensor, a thermometer and a dropping funnel. 4g of sodium sulfate, 25g of copper sulfate and a solution of 660g of sodium acetate in 720ml of water were then added to the solution.
121g of 1-amino-3,4-dimethyl-benzene in powder form were introduced into a mixture of 228ml of concentrated hydrochloric acid, 200ml of water and 400g of ice; 1-amino-3,4-dimethylbenzene hydrochloride crystallized out. A solution of 70g of sodium nitrite in 100ml of water was added dropwise with stirring and ice-cooling in such manner that the temperature did not rise above 5*C. A solution of 130g of sodium acetate in 200ml of water was then added and the ice-cooled diazonium solution thus obtained was added dropwise over 30 minutes to the solution of formaldoxime obtained according to the data in the first paragraph of this Example; during the addition, the temperature was held at 10-15*C. A black tar-like precitate formed. The mixture was stirred for ca 1 hour and then acidified with 200-300 ml of concentrated hydrochloric acid. A furthur 920ml of concentrated hydrochloric acid were added and the mixture was heated at reflux for 2 hours and then distilled with steam. The distillate (ca 5L) was neutralized with 350g of sodium bicarbonate and extracted with 1L of ether. The yellow oily residue obtained after concentration of the ether extract was heated at ca 60*C with stirring for 2 hours with 360ml of a 40% solution of sodium sulfite. About 1300ml of water and 500ml of ether were added to the cooled mixture and the ethereal phase was separated. The aqueous solution was heated at reflux for 30 minutes with 180ml of conc. sulfuric acid and 180 ml of water. The mixture was then extracted with about 1000ml of ether and the extract was dried over sodium sulfate and evaporated to dryness. The yellowish residue was distilled at 97-99*C/10mmHg to yield 59g of pure 3,4-dimethylbenzaldehyde as a colorless liquid that had; nD 23 = 1.5490
A mixture of 100g of 3,4-dimethylbenzaldehyde, 100ml of toluene, 180g of nitroethane, 5 ml of butyl amine, 5ml of glacial acetic acid and 0.35g of paratoluenesulfonic acid was heated at reflux in a 500ml rb flask fitted with a reflux condensor and a water separator. The resulting solution was concentrated under reduced pressure and the oily residue taken up in 100ml of absolute ethanol. Upon cooling to –10*C, yellow crystals were filtered off and washed with ice-cold ethanol and air-dried. 118g of material were obtained.
The alcoholic mother liquor was evaporated to dryness and the residue was taken up in ether. The resulting solution was washed with aqueous sodium carbonate, water, 3N HCl and once again with water and dried over sodium sulfate. The solvent was evaporated and the residue (ca 20g) was distilled under reduced pressure. The fraction boiling at 155-160*C/9mmHg was collected, dissolved in 12ml of absolute ethanol and crystallized at –10*C to yield ca 9g of material. Two crops of material were combined to give 127g of yellow crystals that had; MP: 36-37*C Which after recrystallization from 130ml of methanol gave 121g of pure 3,4-beta-trimethyl-beta-nitrostyrene in the form of light yellow crystals that had; MP: 37-38*C
19.1g of the product above in a mix of 200ml of methanol and 2ml of 48% HBr were hydrogenated at RT in a 500ml hydrogenation flask in the presence of 5g of 5% Pd/C. 0.2mol of H2 was taken up within ca 8 hours, after which time the catalyst was filtered and 5ml of 20% methanolic solution of ammonia were added to the solution. The solution was evaporated to dryness and the residue was taken up in 200ml of ether. Undissolved ammonium hydrobromide was filtered and the rest was hydrogenated in the presence of 15g of raney nickel which had previously been washed with methanol. About 0.2 mol of H2 was taken up in 8 hours. The catalyst was then filtered and the solution was concentrated. The residue was distilled under reduced pressure, the fraction which went over at 110-112*C/10mmHg being separated. 14g of pure 1-(3,4-dimethylphenyl)-2-amino-propane were obtained in the form of a clear liquid that had; nD 23 = 1.5178
The reduction can also be done using LiAlH4
1-(3,4-dimethylphenyl)-2-aminopropane can also be obtained from the nitrostyrene in the following manner:
13.4g LiAlH4 and 360ml of absolute ether were filled into a 1.5L, three-necked flask fitted with a reflux condensor and dropping funnel. A solution of 19.1g of 3,4-beta-trimethyl-beta-nitrostyrene in 240ml of absolute ether was added dropwise with stirring within 2 hours and the mix obtained was boiled under reflux for 2 hours. The mix was then cooled by means of an ice-bath and 90 ml of ice-cooled water were slowly added dropwise. A white granular precipitate formed and was filtered off by suction and thoroughly washed with ether. The ethereal solution obtained was dried over sodium sulfate and concentrated. The residue was distilled at 110-112*C/10mmHg to give 12.2g of pure 1-(3,4-dimethylphenyl)-2-aminopropane.
Also:
The fumarate salt was colorless crystals that had; MP: 187-188*C
The hydrochloride was colorless crystals that had; MP: 169-170*C