AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER
Mar 112015
 

 

Tadalafil skeletal.svg Tadalafil

 

INTRODUCTION Tadalafil is a potent and selective phosphodiesterase-5 (PDE-5) inhibitor, asecondary messenger for the smoothmuscle relaxing effects of nitric oxide,which plays an important role in thevasodilation of erectile tissues.1-3 OralPDE-5 inhibitors have become the preferredfirst-line treatment for erectile dysfunction worldwide.4

 

PREPARATION

 Diastereoselective synthesis of (+)-tadalafil (1)describes a process for the synthesis of tadalafil (1) and itsintermediate of formula5which involves reactingD-tryptophan methylester 2 with a piperonal 3 in the presence of methanol and conc. HCl to
give compound 4 . The later compound is then reacted with chloroacetyl chloride in the presence of NaHCO 3
to afford the intermediate5, which is reacted with methylamine in chloroform to give tadalafil in 88% yield

  Stereoselective synthesis of (+)-tadalafil (1) and(+)-6-epi-tadalafil (8)[20]The target isomeric tadalafil molecule is shown . Thus,D-tryptophan methyl ester reacted with piperonal3under Pictet–Spen-gler reaction condition (TFA/CH2Cl2/MeOH) to furnish two diastereo-mers4and6in 25% and 24% yields, respectively. Condensation of4or6with chloroacetyl chloride provided acylated intermediate 5or7in almostquantitative yield. Subsequent cyclization of5withN-methyl amine inmethanol at 50C for 16 h provided diastereomers tadalafil (1) in 54%yield. Compound1is in full accordance with the literature data {[a]D20¼+71.4 (c 1.00, CHCl3); lit. [a]D20¼+71.2 (c 1.00, CHCl3)}[17,18]. Thus,under the elongated reaction time, 48 h, compound8was obtained fromprecursor7with decreased yield of 21%

depicts an efficient and stereospecific synthesis of tadalafil (1)as well as 12a-epi-tadalafil (11). Pictet–Spengler reaction ofD-trypto-phan methyl ester hydrochloride9with equal molar piperonal byrefluxing for 4 h in nitromethane affordedcis-10-HCl in 98% ee and94% yield. The hydrochloride salt ofcistetrahydro-b-carboline deriva-tivecis-10-HCl was directly treated with 1.5 equiv of chloroacetyl chlo-ride in dichloromethane at 0o
C in the presence of 3 equiv oftriethylamine to formN-chloroacetyl tetrahydro-b-carboline derivative5
in 92% yield. Then compound5reacted with 5 equiv of methylamineovernight in DMF at room temperature to furnish tadalafil1in95% yields.
US PATENT
D. Ben-Zion, D. Dov, United States Patent, US 2006/0276652 A1, 2006.

B.D. Pandurang, B.B. Bharat, S.S. Sachin, P.S. Pranay, United States Patent, US 7, 223,
863 B2, 2007.
FROM L TRYPTOPHAN
X. Sen, S. Xiao-Xin, X. Jing, Y. Jing-Jing, L. Shi-Ling, L. Wei-Dong, Tetrahedron

Asymmetr. 20 (2009) 2090.
S. Xiao-Xin, L. Shi-Ling, X. Wei, X. Yu-Lan, Tetrahedron Asymmetr. 19 (2008) 435
S. Xiao, X. Lu, X.-X. Shi, Y. Sun, L.-L. Liang, X.-H. Yu, J. Dong, Tetrahedron Asymmetr.

20 (2009) 430.
IR OF TADALAFIL
1H NMR OF TADALAFIL

 

13 C NMR OF TADALAFIL

COSY NMR OF TADALAFIL