Here Fan of Shulgin presents you with a world first, a full synthetic procedure for the production of the eagerly anticipated synthesis of tadalafil (cialis) from D-tryptophan...the new Lily treatment for male erectile dysfunction.
This procedure should be of interest to hive chemists. The only watched precursor (AFAIK) is piperonal (which everyone has their favourite method for production). Fan of Shulgin acknowledges fully that this work has been derived from the publication J.Med.Chem 2003, 46, 4533-4542, with some subtle differences. If oxalyl chloride is not available to bee's (initial esterification) then thionyl chloride can be used also...just bee careful.
1. D-Trytophan methyl ester
To a stirred solution of D-Tryptophan (75mmol) in dry methanol (200ml) was added freshly distilled oxalyl chloride (75.5mmol). A single drop of DMF was added as catalyst and stirring was continued for 1 hour subsequent to the cessation of efforvescence. Volatiles were removed by rotary evaporation under reduced pressure providing D-Tryptophan methyl ester quantitatively.
2. Imine formation and Pictet-Spengler ring formation
To a stirred solution of D-tryptophan methyl ester (75mmol) in toluene (150ml) was added piperonal (76mmol) and subjected to reflux under Dean-Stark conditions. After 1 hour, heating was discontinued. A small portion was removed and TLC (5% MeOH in DCM) showed complete consumption of starting material (VERY small spot for residual piperonal). The reaction mixture was allowed to cool to 60C, at which point TFA was added (25mmol) and the reaction mixture was allowed to stir at room temperature for 30h. Quenching with NaHCO3, extraction with EtOAc and drying with MgSO4 afforded 22g of a pale yellow oil which had two product spots by TLC (5% MeOH/DCM). Dry Flash column chromatography (7%MeOH, 1%NH3, 92%DCM) provided 8.29g (26%) of (1R,3R)-methyl 1-(benzo[d][1,3]dioxol-6-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (TOP product spot). The trans (and relatively non-usefull isomer) was eluted very closely as a second product (8.1g).
It should be noted that in DOI:10.1021/jm0300577 (http://dx.doi.org/10.1021/jm0300577)
(J.Med.Chem 2003, 46, 4533-4542) the reaction is performed as a one step reaction in methanol. This was found to be lower yielding (in the hands of this researcher) than the two-step but one pot procedure mentioned here.
3. (1R,3R)-methyl 1-(benzo[d][1,3]dioxol-6-yl)-2-(2-chloroacetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
To the prepared tetrahydroisoquinoline (19.5mmol) in a suspension of NaHCO3 (25mmol) in chloroform (100ml) was added chloroacetyl chloride (22mmol). Stirring was continued at RT for 24 hours, after which 100ml of water was added to the reaction, allowing the complete disolution of base. Organic phase was separated and the aqueous phase extracted with 3 x 75ml DCM. Solvent was removed by rotary evaporation. Column chromatography provided title compound in 85% yield (6.41g).
4. (6R,11aR)-6-(benzo[d][1,3]dioxol-6-yl)-2,3,11,11a-tetrahydro-2-methyl-6H-pyrazino[1,2-b]isoquinoline-1,4-dione (tadalafil, Cialis)
To a commercial solution of ethanolic methylamine (33%, 100ml - huge excess) was added dropwise with stirring 3. This mixture was brought to reflux for 24h. Removal of volatiles under reduced pressure (CAUTION! FUMEHOOD) and standard acid/base extraction (HCl / KOH) provided brown oil which was purified by column chromatography -> title compound in 65% yield.
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Fan of shulgin would like to make it clear that the final product has been identified by 1HNMR and 13C only, and he isnt aware what particular salt will be used in the commercial product. Bioassay has not been carried out because frankly this bee's dick aint limp.
Cool work! See also Post 462736 (missing)
(Rhodium: "The Discovery and Synthesis of Taladafil", General Discourse) an the links therein (https://www.thevespiary.org/rhodium/Rhodium/pdf/jmc-46-4525-2003-the-making-of-tadalafil-1.pdf (https://www.thevespiary.org/rhodium/Rhodium/pdf/jmc-46-4525-2003-the-making-of-tadalafil-1.pdf)
and https://www.thevespiary.org/rhodium/Rhodium/pdf/jmc-46-4525-2003-the-making-of-tadalafil-2.pdf (https://www.thevespiary.org/rhodium/Rhodium/pdf/jmc-46-4525-2003-the-making-of-tadalafil-2.pdf)
).
Most probably piperonal can be replaced by other aldehydes without loss off potency and change in pharmacokinetics.