Dimethylamine → 3-(Dimethylamino)-1-(2-thienyl)-1-propanone
Reaktionsgleichung
[CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([O:11]C1C=CC=C2C=CC=CC=12)[C:6]1[S:10][CH:9]=[CH:8][CH:7]=1.[CH2:22]1N(P(OC2C=CC(OP(N3CC3)(NCCC(C3C=CC=NC=3)=O)=O)=CC=2)(NCCC(C2C=CC=NC=2)=O)=O)C1.C(C1SC=CC=1)(=O)C.CNC.C=O>>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][C:5]([C:6]1[S:10][CH:9]=[CH:8][CH:7]=1)=[O:11]Komponenten
Versuchsvorschrift
Synthesis of duloxetine is described in detail in EP-A-273 658, EP-A-457 559 and EP-A-650965, starting from 2-acetylthiophene, an aminomethylation with dimethylamine and formaldehyde (Mannich reaction) is carried out in step-A. The 3-dimethylamino-1-(2-thienyl)-1-propanone formed is reduced to the corresponding alcohol 1-hydroxy-1-(2-thenyl)-3-dimethylaminopropane by means of complex hydrides in step B. The alcohol is then converted in step C with an alkali metal hydride and 1-fluoro-naphthalene, optionally in the presence of a potassium compound (cf. EP-A-650 965), to the naphthyl derivative, N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine. In the final step D, the amino group is then demethylated by reaction with a chloroformic acid ester, preferably phenyl chloroformate or trichloroethyl chloroformate, optionally in the presence of a mixture of zinc and formic acid (EP-A-457 559), followed by alkaline hydrolysis of the carbamate to give N-methyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine.
Quellen und Nachweise
- ORD-Eintrag
- ord-3176388e8c3546a085e1bb25a56805a4
- Quelldatensatz
- uspto-grants-2013_01
- Patentnummer
- US08362279B2
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