Author Topic: Clandestine Synthesis of Tadalafil (cialis)  (Read 1749 times)

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  • Guest
Clandestine Synthesis of Tadalafil (cialis)
« on: October 29, 2003, 10:45:00 PM »
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:


(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.


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.


  • Guest
Cool work! See also Post 462736 an the links...
« Reply #1 on: October 30, 2003, 01:02:00 AM »
Cool work! See also

Post 462736 (missing)

(Rhodium: "The Discovery and Synthesis of Taladafil", General Discourse)
an the links therein (


Most probably piperonal can be replaced by other aldehydes without loss off potency and change in pharmacokinetics.


  • Guest
Substituting piperonal for other aldehydes
« Reply #2 on: October 30, 2003, 06:20:00 PM »
I think one would have to be very careful in changing piperonal to other aldehydes.....there could be very dramatic changes in selectivity receptor selectivity, and since PDEases have important cardiovascular role, i certainly wouldnt try these out in vivo without proper biochemical evaluation.



  • Guest
From the second paper linked by Lilienthal:...
« Reply #3 on: October 30, 2003, 09:22:00 PM »
From the second paper linked by Lilienthal, p. 4536:

"Substitution on the C-6 aromatic ring with electrondonating groups generally increased inhibitory potency compared with the unsubstituted compound 11b. The best results were obtained with the 4-methoxy (cis-11a) and 3,4-methylenedioxy substituents (cis-11c) where an 18-fold improvement in PDE5 inhibitory potency was observed, compared to the unsubstituted analogue 11b. In contrast, introduction of strong electron-withdrawing groups such as cyano (cis-11d) at the 4-position of the phenyl ring resulted in a marked decrease in PDE5 inhibitory activity. Introduction of the weaker electronwithdrawing chlorine atom in the para position (cis-11e) retained the PDE5 inhibitory activity but totally lost functional activity in the cellular assay. Substitution at the 4-position with a methyl group (cis-11f) also resulted in improved potency vs PDE5 compared with the unsubstituted compound 11b. Disubstitution of the phenyl ring at positions 3 and 4 by methoxy groups (cis-11g) led to a complete loss in activity on PDE5. Interestingly, the conformationally constrained 3,4-methylenedioxy analogue, cis-11c, retained good PDE5 inhibitory potency, suggesting that 3,4-substitution needs to be sterically compact."


  • Guest
Interesting chemistry, but is this cynical
« Reply #4 on: February 09, 2004, 04:59:00 AM »


  • Guest
Fair Point
« Reply #5 on: February 10, 2004, 03:02:00 AM »
Dear Capt.USA,

I understand your frustration to some point. I agree....this is not phenethylamine or tryptamine chemistry.  I do however suggest that reactions such as the pictet-spengler reaction (which my posting contained) may be of more immediate relevance when Dr Shulgin releases his next book.

To your second point, i very much am a fan of shulgin...howerver..pihkal stands alone as a piece of work.  I dont think it would be of any use repeating a reaction from that beautiful work just to post and gain karma.  As Dr Shulgin said himself...the loss of his analytical license was of no consequence....since he is not interested in synthesising illegal compounds....just new ones.  I too am interested in pushing FORWARD the boundaries, making new and interesting compounds.  I for one know that producing something like 2C-B would be like winning the lottery, but the realms of human consciousness wont be pushed forward unless we try!

As for cialis.  I guess i just wanted people to know that it could be done in a clandestine setting, using many of the chemicals that bees would already have. 

Fan of Shulgin.