一种手性双膦配体在不对称催化氢化制备度洛西汀中的应用研究

Duloxetine production: A novel chiral biphosphine ligands in asymmetric catalytic hydrogenation

度洛西汀是5-羟色胺和去肾上腺素再摄取抑制剂,第三代抗抑郁药.应用手性双膦配体(P-Phos)不对称催化氢化制备度洛西汀的关键中间体,在40℃、3 MPa H2、异丙醇为溶剂的条件下使3-(二甲胺基)-1-(2-噻吩基)-1-丙酮转化为(S)-3-(二甲胺基)-1-(2-噻吩基)-1-丙醇,并取得了极好的收率(99%)和对映选择性(94%ee),产品经重结晶,光学纯度>99%ee.度洛西汀全合成总收率为87%.

Duloxetine is a serotonin and norepinephrine reuptake inhibitor, the third generation of antidepres- sants. In this study, we utilize P-Phos as the chiral phosphine ligand for the preparation of duloxetine via cata- lytic asymmetric hydrogenation reaction. The results indicate that the optimized reaction conditions for this reac- tion are： H2 is 3 MPa, the solvent is isopropanol, 3-（ dimethylamino）-l-（2-thienyl）-l-propanone is converted to （S）-3-（ dimethylamino）-l-（2-thienyl）-l-propanol at 40 ℃. This reaction has excellent reaction yield （99%） and enantioselectivity （94% ee）, the optical purity of desired product can be up to 99% ee by con- ducting a single recrystallization experiment. Finally, the total synthesis yield of duloxetine is 87%.