Abstract
The synthesis of (±)-duloxetine-d6, which is needed for metabolism studies, has been achieved in four steps. The product of a Mannich reaction of 2-acetylthiophene, dimethylamine-d6 hydrochloride and paraformaldehyde-d2 was reduced with NaBH4 to yield an octadeuterated aminoalcohol that was etherified with 1-fluoronaphalene/NaH. The final step was a demethylation (removal of a CD3 group) using PhOCOCI/ethyldiisopropylamine. The pentadeuterated product was formed in 51% overall yield and with a chemical purity of 99.3%.
Keywords
References
1.
Raskin J.
,
Wiltse G.
,
Dinkel J.
,
Walker J.
,
Desaiah D.
and
Katona C.
, J. Clin. Psychopharmacol. , 2008 , 28 , 32 .
2.
Kanbayashi Y.
,
Inagaki M.
,
Ueno H.
and
Hosokawa T.
, Med. Oncol. , 2017 , 34 , 137 .
3.Cymbalta [package insert]. Indianapolis, IN: Eli Lilly and Company, 2004 .
4.
Tong X.
,
Ita I.
and
Wang J.J.
, J. Pharm. Biomed. Anal. , 1999 , 20 , 773 .
5.
Guo X.
,
Chen X.
,
Li L.
,
Shen Z.
,
Wang X.
,
Zheng P.
,
Duan F.
,
Ma Y.
and
Bi K.
, J. Chromatogr. B, Analyt. Technol. Biomed. Life Sci. , 2008 , 873 , 51 .
6.
Pan G.
,
Wang X.
,
Huang Y.
,
Gao X.
and
Wang Y.
, J. Pharm. Biomed. Anal. , 2010 , 52 , 105 .
7.
Guo L.
,
Duan L.
,
Dong X.
,
Dou L.L.
,
Zhou P.
,
Liu E.H.
and
Li P.
, J. Chromatogr. B , 2014 , 973 , 33 .
8.
Deeter J.
,
Frazier J.
,
Staten G.
,
Staszak M.
and
Weigel L.
, Tetrahedron Lett. , 1990 , 31 , 7101 .
9.
Staszak M.
,
Staten G.
and
Weigel L.
, European Patent: 0457559, issued 1991 .
10.
Berglund R.A.
, U.S. Patent: 5 362 886, issued 1994 .
11.
Berglund R.A.
, European Patent: 0650965, issued 1995 .
12.
Liu H.
,
Hoff B.H.
and
Anthonsen T.
, Chirality , 2000 , 12 , 26 .
13.
Fabian K.
,
Niesert C.P.
,
Kralik J.
and
Glüsenkamp K.H.
, U.S. Patent: 0 122 405, issued 2006 .
14.
Kamal A.
,
Khanna G.B.R.
,
Ramu R.
and
Krishnaji T.
, Tetrahedron Lett. , 2003 , 44 , 4783 .
15.
Gao L.
,
Zhu F.
and
Song D.
, Chin. J. New Drugs , 2005 , 14 , 74 .
16.
Yu X.
,
Wen X.
,
Tang J.
,
Mao Q.
and
Shen Y.
, Chin. J. Pharm. , 2006 , 37 , 367 .
17.
Bymaster F.P.
,
Beedle E.E.
,
Findlay J.
,
Gallagher P.T.
,
Krushinski J.H.
,
Mitchell S.
,
Robertson D.W.
,
Thompson D.C.
,
Wallace L.
and
Wong D.T.
, Bioorg. Med. Chem. Lett. , 2003 , 13 , 4477 .
18.
Meth-Cohn O.
and
Gronowitz S.
, Acta. Chem. Scand. , 1966 , 20 , 1577 .
19.
Fujima Y.
,
Ikunaka M.
,
Toru Inoue A.
and
Matsumoto J.
, Org. Process. Res. Dev. , 2006 , 10 , 905 .