Method of production of essentially pure melatonin and the method of solubilizing melatonin in water

Abstract

A method of synthesizing an indole derivative of the tryptamine type particularly . .melatonine,.!. .Iadd.melatonin .Iaddend.comprising the steps of 1) reacting potassium phthalimide and 1,3-di-bromopropane to obtain 3-bromopropylphthalimide; 2) reacting 3-bromopropylphthalimide with sodium acetoacetic ester in ethanol to obtain ethyl-2-acetyl-5-phthalimidopentanoate; 3) reacting the product from step 2) with diazo-p-anisidine to obtain 2-carboxyethyl-3-(2-phthalimidoethyl)-5-methoxy-indole; 4) reacting the 2-carboxyethyl-3-(2-phthalimidoethyl)-5-methoxy-indole with 2N/NaOH and then 20% H 2 SO 4 to obtain impure 5-methoxytriptamine, which is purified by means of hexamethyldisilazane. The mono and disubstituted derivatives are obtained and the monosubstituted derivative is hydrolyzed with aqueous methanol and then recrystallized from ethanol. The N-acetyl derivative is prepared by reaction with acetic anhydride. . .Melatonine.!. .Iadd.Melatonin .Iaddend.of high purity is obtained for prophylaxy and also against AIDS (Acquired Immuno Deficiency Syndrome).

We claim: 
     
       1. The method of solubilizing . .melatonine.!. .Iadd.melatonin .Iaddend.in water which consists of mixing . .melatonine.!. .Iadd.melatonin .Iaddend.with adenosine in a ratio of one mole of . .melatonine.!. .Iadd.melatonin .Iaddend.to four moles of adenosine whereby a water soluble product is obtained. .Iadd.2. A method of preparation of melatonin having a high degree of purity which consists of the steps of: a) reacting potassium phthalimide with dibromopropane, whereby 3-bromopropylphthalimide is obtained;   b) reacting 3-bromopropylphthalimide from step a) with acetoacetic ester in the presence of sodium ethoxide whereby ethyl 2-acetyl phthalimido-pentanoate is obtained;   c) reacting said ethyl 2-acetyl phthalimido pentanoate from step b) with the diazonium salt of p-anisidine whereby 2-carboxyethyl 3-(2-phthalimidoethyl) 5-methoxy indole is obtained;   d) reacting said 2-carboxyethyl 3-(2-phthalimidoethyl) 5-methoxy-indole from step c) first with sodium hydroxide and then with sulfuric acid whereby crude 5-methoxy-tryptamine is obtained;   e) reacting said crude 5-methoxy-tryptamine from step d) with hexamethyl disilazane to obtain a mixture of mono- and disubstitution products and hydrolyzing said mixture with aqueous methanol to obtain essentially pure 5-methoxy-tryptamine;   f) reacting said essentially pure 5-methoxy-tryptamine from step c) with acetic anhydride to obtain crude melatonin and purifying said crude melatonin by chromatography on silica gel and first eluting with methylene chloride followed by eluting with methylene chloride and acetone to obtain a solution, concentrating said methylene chloride and acetone solution to obtain a solid and recrystallizing said solid whereby purified melatonin   
     
     
        is obtained. .Iaddend..Iadd.3.  The method according to claim 2 wherein said step d) is carried out by refluxing at 135° C. for 21/2 hours until complete solution is obtained, then adding a 20% (v/v) H 2  SO 4  solution and further refluxing for four hours. .Iaddend..Iadd.4. The method according to claim 3 wherein after refluxing with said 20% sulfuric acid, the solution is cooled to let phthalic acid precipitate and filtering off said phthalic acid. .Iaddend..Iadd.5. The method according to claim 4 wherein after said phthalic acid is filtered off, sodium hydroxide is added and crude 5-methoxytryptamine is extracted with 
     
     
        methylene dichloride. .Iaddend..Iadd.6.  The method according to claim 2 wherein said step f) is carried out by refluxing for 12-14 hours said crude 5-methoxytryptamine with hexamethyl-disilazane, to obtain the mono and di-silyl substitution products, then distilling the solution under normal pressure so as to recover excess hexamethyl disilazane and hydrolyzing the silyl substitution products with aqueous methanol whereby essentially pure 5-methoxytryptamine is provided. .Iaddend.