Harmine synthesis

Abstract

Methods for the synthesis of harmine comprise reacting harmaline with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in the presence of a diacid catalyst. In an embodiment, the synthesis is carried out using a reaction mixture of harmaline, DDQ, THF solvent, and succinic acid; the reaction is carried out under an inert atmosphere with refluxing for a period of 4-12 hours.

Claims

1. A method of synthesizing harmine comprising the steps of reacting a reaction mixture comprising harmaline with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in a compatible solvent and in the presence of an acid catalyst, and thereafter recovering harmine.

2. The method of claim 1, said acid catalyst being a diacid.

3. The method of claim 2, said diacid being selected from the group consisting of saturated C2-C10 diacids, where the carbon chain may be linear, branched, or cyclic.

4. The method of claim 3, said diacid selected from the group consisting of C2-C10 linear diacids.

5. The method of claim 4, said diacid selected from the group consisting of C3-C6 linear diacids.

6. The method of claim 1, where said DDQ is present in a molar excess as compared with harmaline.

7. The method of claim 1, said reaction carried out under an inert atmosphere.

8. The method of claim 1, including the step of refluxing said reaction mixture for a period of from about 4-12 hours.

9. The method of claim 1, said recovery step comprising the step of purifying the reaction product of the reaction using chromatography.

10. The method of claim 1, said solvent selected from the group consisting of THF, dichloromethane, ethyl acetate, toluene, ethers such as dibutyl ether or cyclopentyl methyl ether, dimethoxyethane, acetonitrile, dichloroethane, and mixtures thereof.

11. The method of claim 10, wherein said solvent is THF.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

(1) Generally speaking, the invention pertains to a synthesis of harmine involving acid-catalyzed dehydrogenation of harmaline by DDQ to give substantially quantitative yields of harmine. The overall reaction is:

(2) ##STR00001##

(3) In the synthesis, the DDQ is typically present in a molar excess as compared with the harmaline. The acid catalyst is preferably a C2-C10 saturated diacid, where the carbon chain may be linear, branched, or cyclic. The most readily available diacids are the linear dicarboxylic acids, such as:

(4) TABLE-US-00001 Common name Systematic IUPAC name Structure Oxalic acid ethanedioic acid Malonic acid propanedioic acid Succinic acid butanedioic acid Glutaric acid pentanedioic acid Adipic acid hexanedioic acid Pimelic acid heptanedioic acid Suberic acid octanedioic acid Azelaic acid nonanedioic acid Sebacic acid decanedioic acid 0
The solvent can be selected from any non-interfering solvent which will support the reaction. A typical example is tetrahydrofuran (THF), although other possibilities exist.

(5) The reaction is preferably carried out in an inert atmosphere, typically nitrogen gas, for a period of from about 4-12 hours, with refluxing. The crude reaction mixture is then treated to recover the harmine product using solvent extraction and chromatography.

EXAMPLES

Example 1

(6) In this example, harmaline (previously dried using a Dean-Stark apparatus under N.sub.2) and DDQ were reacted in the presence of succinic acid and dried THF solvent (THF dried by boiling with sodium metal and benzoquinone under N.sub.2).

(7) Specifically, harmaline was added to a round-bottom flask, followed by 1.5 equivalents of DDQ and an excess of succinic acid, in a glove bag under nitrogen. After initial mixing, the flask was connected with a condenser and moved to a hood. The THF was then added to the flask and the mixture was refluxed for 8 hours under N.sub.2.

(8) After refluxing, the reaction mixture was cooled to room temperature and 1M sodium hydroxide was added with stirring for 5 minutes. The pH of the aqua layer was measured to confirm that the pH was basic, and the organic layer was separated from the aqua layer with 5 equivalents of acetone. This separated solution was then concentrated using a rotary evaporator to provide a crude solid. This solid was dissolved in dichloromethane, followed by vacuum filtration on a celite pad/cake to remove solid impurities. The organic solution was then dried over anhydrous ammonium sulfate (Na2SO4) and concentrated using the rotary evaporator to obtain a dark brown solid. Purification was performed using column chromatography with a solvent system of 10% methanol in dichloromethane. The purified product was analyzed using NMR for the presence of harmaline and harmine. No harmaline characteristic peaks were observed in the final product, confirming the essentially quantitative production of harmine.

(9) The same procedure was carried out except that no succinic acid or other diacid catalyst was used. This resulted in a final product containing substantial amounts of harmaline. Thus, performing the reaction in the absence of acid catalyst resulted in incomplete conversion to harmine.

(10) While not wishing to be bound by any theory, it is believed that the conversion synthesis of harmine using harmaline as a starting reactant involves a stepwise reaction according to the following reaction scheme:

(11) Step 1: Conversion of DDQ to DDQH

(12) ##STR00011##

(13) Step 2: Dehydrogenation of Harmaline by DDQH and 3-carboxypropanoate

(14) ##STR00012##

Example 2

(15) The above Example 1 synthesis of harmine was repeated three times except that oxalic, maleic, and glutaric acids were used in lieu of succinic acid. All three syntheses were successful and yielded high levels of conversion of harmaline to harmine. However, succinic is generally less expensive than these other diacids, and is therefore preferred.