N-Methyl-3,4-dihydroxyphenylalanine (CAS NO.: 53663-27-7), which is known as Alanine, β-(3,4-dihydroxyphenyl)-N-methyl-, could be produced through the following synthetic routes.
A. 5-(3-Methoxy-4-hydroxybenzal)creatinine (CAS NO.: 29974-40-1)(I). In a large Pyrex test tube (51 mm. outside diameter and 200 mm. long) is placed an intimate mixture of 11.3 g. (0.1 mole) of creatinine and 24 g. (0.16 mole) of vanillin. The tube is placed in an oil bath, which is then heated to 170°, and the mixture is melted while it is constantly agitated. The temperature of the mixture reaches 155° in about 10 minutes; reaction then begins, and water is evolved. After 3–5 minutes longer, evolution of water ceases, and the mixture solidifies. The tube is heated for 3 minutes more, and then it is removed from the bath and allowed to cool.
When the temperature has fallen to 50–60°, 50 ml. of ethanol is added and the mixture is heated gently by occasional immersion in the warm oil bath. The solid partially disintegrates and forms a suspension. The suspension is filtered, and the solid remaining in the tube is warmed with a second 50-ml. portion of ethanol. This operation is repeated until all the orange-colored condensation product has been transferred to the filter. The material on the filter is then washed with three successive 30-ml. portions of water at 60°.
After drying, the crude product weighs 24 g. (95%), melts at 261–263°, and is suitable for use in the next step. A pure product, which melts at 273°, may be obtained by recrystallizing the crude material from acetic acid.
B. 5-(3-Methoxy-4-hydroxybenzyl)creatinine (II). To a suspension of 24 g. (0.1 mole) of the crude condensation product in 150 ml. of water, contained in a 500-ml. beaker, there is added, with continuous agitation, 180 g. of 3% sodium amalgam. The amalgam is added in six portion, at intervals of 5 minutes. The solid dissolves, and the initial orange-red color of the solution slowly fades as the reduction proceeds. With good agitation, decolorization is complete in 45–60 minutes, if the starting material is pure. When the crude condensation product is used, the color of the solution fades to a faint, but permanent, yellow tint, which should mark the end point of the reduction.
The solution is decanted from the mercury and filtered from suspended impurities. The filtrate is stirred and is acidified with hydrochloric acid to pH 6.6, phenol red being used as the indicator. After standing for 2 hours at 0°, the mixture is filtered and the solid is washed with a little cold water and dried. The product (free base) is microcrystalline, weighs 17.5–18 g. (72–74%), and usually melts at 167–169°. After solidification from fusion, the substance melts at 226–228°. When recrystallized from water, the substance melts at 231–233°. The crude product may be used for the subsequent hydrolysis.
C. N-Methyl-(3-methoxy-4-hydroxyphenyl)alanine (III). In a 2-l. round-bottomed flask, 18 g. (0.07 mole) of the crude reduction product is refluxed for 12 hours with a solution of 180 g. of crystalline barium hydroxide in 270 ml. of water. The hot solution is diluted with 1.2 l. of water, and the barium is precipitated by addition of 250–270 ml. of 6 N sulfuric acid. The precipitated barium sulfate is separated by centrifuging and washed with two 100-ml. portions of water; the combined water; solutions are evaporated under reduced pressure at 50° to a volume of about 50 ml. The acid solution is made alkaline to litmus by addition of about 10 ml. of a 12% solution of ammonium hydroxide in water. After standing for 24 hours at 0°, the mixture is filtered, and the solid is washed with cold water and dried. The yield is 12 g. (74%). On rapid heating, the solid melts at 273–275°. When recrystallized from water, the substance melts at 276–278°. The crude product may be used for the next step.
D. N-Methyl-3,4-dihydroxyphenylalanine (CAS NO.: 53663-27-7)(IV). In a carbon dioxide atmosphere, 12 g. (0.05 mole) of the methoxy compound is boiled gently for 3 hours with 24 g. of red phosphorus and a mixture of 60 ml. of acetic anhydride and 60 ml. of hydriodic acid (sp. gr. 1.7). The phosphorus is then removed by filtration and washed with 25 ml. of 50% acetic acid. The filtrates are combined and, in a current of carbon dioxide, are evaporated to a syrup at 50° under 35 mm. pressure. A 60-ml. portion of warm water is then added, and the solution is evaporated as before. The residue is dissolved in 100 ml. of water, and dilute ammonia (10% by volume) is added until the solution does not change Congo red paper to blue. The mixture is allowed to stand for 2 hours at 0°, and then the white crystalline precipitate is filtered. The precipitate is washed on the funnel with a little water containing sulfur dioxide, and is dried by washing with ethanol and ether. The product weighs 9.5 g. (82%). When slowly heated it becomes slightly brown at 230° and melts at 282–283°; when rapidly heated it becomes slightly brown at 255–260° and melts at 290–292°.
This material may be purified by boiling 1 g. of it with 50 ml. of water containing sulfur dioxide, filtering the solution, and keeping the filtrate at 0° for 24 hours. The purified product (0.74 g.), when slowly heated, becomes slightly brown at 245° and melts at 287°; when rapidly heated it becomes slightly brown at 260° and melts at 298–300°.
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