Tadalafil , synthesis

Impressive examples of CIAT processes are shown in Schemes 2.10 and 2.11. In an early synthesis of tadalafil, a Pictet-Spengler reaction was used to prepare the c -6-carboline intermediate 35 in 42% yield (TFA, CH2CI2, 4°C/5 days chromatography) or 58% yield (AcOH, H2O, 50°C/4 days crystalhzation) (Daugan, 1999 Orme et al., 2005). A much improved route utilizing CIAT is shown in Scheme 2.10 (Orme et al., 2005). A dynamic equilibrium was set up between 35 and 36 and the undesired dia-stereomer 36 stayed dissolved in the reaction medium while the product 35 crystallized out, driving the process to completion and raising the yield to 92%. 

Discovery and synthesis of sildenafil 13.3 Synthesis of vardenafil 13.4 Synthesis of tadalafil 13.5 References... 

Scheme 8.1 describes a process for the synthesis of tadalafil (1) and its intermediate of formula 5 which involves reacting D-tryptophan methyl ester 2 with a piperonal 3 in the presence of methanol and cone. HCl to give compoimd 4. The later compound is then reacted with chloroacetyl chloride in the presence of NaHCOs to afford the intermediate 5, which is reacted with methylamine in chloroform to give tadalafil in 88% yield. 

Scheme 8.3 depicts an efficient and stereospecific synthesis of tadalafil (1) as well as 12a-epf-tadalafil (11). Pictet-Spengler reaction of D-trypto-phan methyl ester hydrochloride 9 with equal molar piperonal by refluxing for 4 h in nitromethane afforded cfs-lO-HCl in 98% ee and 94% yield. The hydrochloride salt of cis tetrahydro-p-carboline derivative a s-10-HCl was directly treated with 1.5 equiv of chloroacetyl chloride in dichloromethane at 0°C in the presence of 3 equiv of triethylamine to form N-chloroacetyl tetrahydro-p-carboline derivative 5 in 92% yield. Then compoimd 5 reacted with 5 equiv of methylamine overnight in DMF at room temperature to furnish tadalafil 1 in 95% yields. 

The first synthesis of tadalafil (1) (Cialis) from /.-tryptophan [24]... 

Electrophilic substitutions on the indole ring overwhelmingly favor the C3 position. However, when the energy outcome is favorable, C2 electrophilic substitutions do occur, especially for intramolecular substitutions. For instance, in the synthesis of tadalafil (Cialis), the Pictet-Spengler reaction is used to prepare the cw-p-carboline where the C2 electrophilic substitution takes place. In the presence of trifluoroacetic acid (TFA), Z)-tryptophan methyl ester is condensed with piperonal. The C2-carbon of the indole adds to the resulting iminium ion to give a mixture of the cA-B-carboline and the... 

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