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01-11-04 22:05
No 481878
(Rated as: excellent)
This patent was referenced in :
Post 219601 (Cyrax: "Synthesis of amphetamines", Methods Discourse)
Patent GB360266
Manufacture of Trialkoxy Derivatives of Phenylethylamine
Much of the excess rhetoric has been left out of this text. Only chemical information has been included.
Abstract: The 3,4,5-trialkoxynitrostyrenes are obtained by converting the corresponding trialkoxybenzoic acids, for example by way of their halides, into the corresponding aldehydes and condensing the latter with nitromethane.
Example 1:
127g of 3,4,5-triethoxybenzoic acid (Ber. d.d. chem. Ges., 1884, Vol. 17, pg. 2099) are dissolved in thionyl chloride and the solution is heated for some time on the water-bath. After distilling the excess of thionyl chloride the residue is fractionated in a vacuum. The triethoxybenzoyl chloride boils at 153*C at 1mm pressure and when cooled solidifies to a white crystalline mass.
81.6g of triethoxybenzoyl chloride are dissolved in 400ml of toluene, the solution is mixed with 25g of barium sulfate-palladium catalyst (2% strength) and the solution is reduced by passing hydrogen through it at 110-115*C. The reduction is finished when no more hydrogen chloride is evolved. After filtration of the catalyst the toluene is distilled, the residue solidifies and is re-crystallized from petroleum ether.
The triethoxybenzaldehyde forms white crystals which melt at 69-70*C.
A solution of 71.4g of the aldehyde and 22g of nitromethane in 150ml of alcohol is mixed in small portions while cooling with a solution of 30g of KOH in 30 ml of water and 60ml of methanol and the whole is then allowed to stand for a quarter of an hour at the ordinary temperature; it is then poured into 800ml of HCl acid of 10% strength, cooled with ice, whereupon the nitrostyrene separates in the form of a yellow precipitate. When recrystallized from alcohol it forms yellow crystals which melt at 108-109*C.
To a suspension of 40g of triethoxynitrostyrene in 700*C of alcohol, there is added a solution of 1g of Palladious chloride in 40ml of water and 25ml of conc. HCl. The solution is then reduced with H2 at 15*C in a shaking flask.
When absorption of hydrogen is finished, the separated palladium is filtered and the alcohol distilled until nearly to dryness. The residue is made alkaline and extracted with ether. The ether is distilled and the residue extracted in dilute HCl. The portion insoluble in acid is separated by means of ether and the base is precipitated by means of NaOH, extracted and fractionated. At 140*C at 1mm pressure, colorless triethoxyphenylethylamine distills. The HCl salt forms white crystals soluble in water and of MP: 178-179*C.
Example 2:
12.3g of the sodium salt of syringaic acid are heated in 120ml of dilute alcohol with 6.8g of n-butyl bromide on the water bath. After acidification with dilute hydrochloric acid, the 4-n-butoxy-3,5-dimethoxybenzoic acid crystallizes. When recrystallized from alcohol it has a MP: 104-105*C.
The acid is then converted with thionyl chloride in the manner described in the foregoing Example into the acid chloride boiling at 160*C at 4mm pressure. By reducing the chloride with Pd and hydrogen there is obtained the aldehyde which forms white crystals of MP: 54-55*C. With nitromethane and an alcoholic solution of potassium, the aldehyde is transformed into the 4-butoxy-3,5-dimethoxynitrostyrene, forming yellow crystals of MP: 94-96*C.
10g of the nitrostyrene are dissolved in 200ml of glacial acetic acid containing 1.5g of HCl. After addition of 0.2g of Palladious chloride as a catalyst, the whole is reduced with hydrogen at ordinary temperature. The glacial acetic acid is distilled in a vacuum and the crystalline residue, which is the hydrochloride of the amine is recrystallized from ethyl acetate. It forms white crystals of MP: 153-154*C. Which are easily soluble in water.
In place of palladious chloride also colloidal palladium, chloroplatinic acid, colloidal platinum, platinum black, etc. may be used.
Example 3:
The 4-benzyloxy-3,5-dimethoxybenzoic acid is produced from the sodium salt of syringaic and benzylchloride in a manner analogous to that described for the production of the n-butoxy compound used in the preparation of Example 1. It forms white crystals of MP: 159-160*C. By chlorinating with thionyl chloride, the 4-benzoyloxy-3,5-dimethoxybenzoyl chloride of MP: 95*C is obtained, which is reduced with hydrogen and palladium to the benzyloxy-3,5-dimethoxybenzaldehyde of MP: 65-66*C. By condensation with nitromethane, the 4-benzyloxy-3,5-dimethoxynitrostyrene is obtained which when recrystallized from alcohol, has MP: 134-135*C.
30g of 4-benzyloxy-3,5-dimethoxynitrostyrene are dissolved in 90ml of glacial acetic acid and 180ml of alcohol and then mixed, while cooling, with 30g of Zn dust. After filtering the excess Zn dust, the residue is mixed with water and extracted several times with ether. After the ether has been distilled, the residue, consisting of the oxime of the 4-benzyloxy-3,5-dimethoxy-1-phenylacetal
The solution thus obtained, after addition of water, is extracted with ether for the purpose of removing non-basic impurities, then made strongly basic and the oil which separates is dissolved in ether. The ethereal solution is dried and mixed with alcoholic HCl. The HCl salt 4-benzyloxy-3,5-dimethoxyphenylethylamin
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