Final Condensation Reaction for THC and Variants
The last stage in the preparation of THC and the variants consists of a simple condensation of the appropriate 5-(alkyl)-resorcinol (which forms the upper right-hand ring in the structural diagram) with one of the following materials (forming the upper left-hand ring, and in combination with the hydroxy-group of the resorcinol also the lower center ring.
(A). Citral (Gives a yield of about 1O% in the THC-A series, or 5% to 10% in the THC-B series).
(B). (-)-Verbenol (Gives a 38% yield of THC-B or 21% of THC-A)
(C). (-)-2-carbethoxy-5-methyl-cyclohexane (For the THC-C series; yields of 20% to 50%. This may be considerably improved by use of boron trifluoride etherate.)
(D). (+)-p-2,8-menthadien-1-ol (Using small quantities gives a yield of 50% in THC-B series; this may be lowered with larger batches.)
Although Citral is commercially available it is recommended that because of the relatively great amount of labor involved in preparing the co-reactant 5-(alkyl)-resorcinol one of the other agents be used. (-)-Verbenol gives a good yield and can be readily prepared by well tested methods from cheap Canada Balsam. The other reactants can be used but the preparations are a little longer or may require some experimentation.
In the preparation of the THC-C series THC and all of the variants are obtained by similar condensations, simply altering the 5-(alkyl)-resorcinol. It can be expected that the same results will be obtained with the condensations producing the THC-A and THC-B isomers
Use of the different co-reactants with the resorcinols has been described by different authors using different techniques and catalysts. In many cases details as originally given are fragmentary and the more complete conditions given here have been established by experiment or analogy with similar reported reactions. Some experimentation may be needed to obtain maximum yields. Included in the following sections, dealing separately with each of the co-reactants listed, is the preparation of the co-reactant.
The THC-s obtained as described following are physiologically active, but somewhat unstable and will lose potency over a period of months. They should be converted to the acetate esters unless used immediately. For the same reason of instability no effort should be made to purify the crude products without first converting them to the acetate esters, which can be purified without serious decomposition.
Acetylation is accomplished by refluxing with excess mixture of acetic anhydride and anhydrous sodium acetate. Anhydrous sodium acetate is available commercially or it can be prepared by fusing the crystalline hydrate in a porcelain or metal dish. About 5 grams sodium acetate are used for each 200 grams. acetic anhydride; about three volumes of the mixture are used per volume of material to be acetylated.
After refluxing for three hours (Reference 219) the product is isolated as a solid or oil by pouring onto a mixture of crushed ice and dilute acid. The solid or oil is dissolved in ether then shaken successively with dilute hydrochloric acid, dilute sodium carbonate, water, and finally dried with anhydrous calcium chloride or Drierite. After distilling off the ether the material is suitable for many uses.
If further purification is desired it can sometimes be accomplished by dissolving the crude in ethyl alcohol (not too much slightly warm but not hot alcohol is used) and standing 4-7 days in the refrigerator at about 4 deg. C. Crystals can be filtered out and the mother-liquor partially evaporated and refrigerated again.
It is likely that better results will be obtained in the acetylation by using the recent method of Gaoni (Israel J. Chemistry, 6, page 679, 1968). In his work Gaoni simply allowed a mixture of the THC (0.5 gram), pyridine (5 ml.), and acetic anhydride (1 ml.) to stand overnight at room temperature.
Aaron (Reference 219) used a more elaborate method to obtain pure material which is probably superior but may be difficult to work with larger quantities. He dissolved the acetylated material in petroleum ether (the quantities involved were about 3-5 grams) and poured the solution into a chromatographic column measuring one inch in diameter and 3.5 inches long (Reference 199) composed of silicic acid. The product was isolated by eluting from the column with a mixture of petroleum ether (98 parts) and diethyl ether (2 parts). The first 100 ml. of eluent was fluorescent and collected separately; the product was collected in the second 100 ml. of eluent from which it was obtained by distillation under reduced pressure to remove the solvent (even though these solvents boil at low temperatures reduced pressure is used to avoid any heat which might cause formation of inactive isomers). The pure product is not distilled even under reduced pressure.
If desired the silicic acid column can be washed out with 50% petroleum ether-diethyl ether and the residue after evaporation combined with the fluorescent forerun residue. Possibly some small amounts of product can be obtained by careful purification of these materials.
The following condensation reactions have been described for the use of one mole quantities of the required 5-(alkyl)-resorcinol. The corresponding weights and formulas are as follows. (The formulas can be used to locate any recent and improved syntheses in the Chemical Abstracts formula index).
THC: (C11 H16 O2) 180 grams
THC-II: (C12 H18 O2 ) 194 grams
THC-III: (C15 H24 O2 ) 236 grams
THC-IV: (C16 H26 O2) 250 grams
THC-V: (C15 H24 O2 ) 236 grams
THC-VI: (C16 H26 O2) 250 grams
An experienced chemist may be able to prepare the isopropenylic terpene required as co-reactant with the 5-(alkyl)-resorcinol by use of the method of Vig (J. Indian Chem. Soc. 45, page 734, page 1026, 1968). Care is needed that the required isomer is obtained.
Intermediate Ketone: Method II
Condensation with Citral