A Practical Synthesis of the Antidepressant (S)-Duloxetine

Experimental

Preparation of 3-Chloro-1-(2-thienyl)-1-propanone (2). The β-chloro ketone 2 was prepared through Friedel-Crafts acylation of thiophene with 3-chloropropionyl chloride in the presence of AlCl3.11 Yield: 19.2 g (95%); 1H NMR (300 MHz, CDCl3) δ 7.74 (dd, 1H, J = 3.8, 1.1 Hz), 7.67 (dd, 1H, J = 4.9, 1.1 Hz), 7.14 (dd, 1H, J = 5.0, 3.8 Hz), 3.90 (t, 2H, J = 6.8 Hz), 3.40 (t, 2H, J = 6.8 Hz); MS (EI) m/z (%) 174 (M+, 58), 139 (50), 111 (100), 83 (30).

Preparation of (R)-2-[(1,3,2-Dioxaborolan-2-yloxy)di-phenylmethyl] pyrrolidine, (R)-3b. The (R)-3b was pre-pared as a white crystalline precipitate by heating equimolar amount of (R)-α,α-diphenyl-2-pyrrolidinemethanol, ethylene glycol, and triisopropyl borate in toluene.10b Yield: 1.13 g (90%); mp 270 °C; (c 0.12, CHCl3); 1H NMR (300 MHz, DMSO-d6) δ 7.72 (d, J = 7.2 Hz, 2H), 7.52 (d, J = 7.2 Hz, 2H), 7.06-7.28 (m, 6H), 6.69 (t, 1H, NH), 4.54 (m, 1H), 3.67-3.79 (m, 2H), 3.55-3.63 (m, 2H), 3.02-3.11 (m, 1H), 2.86-2.97 (m, 1H) 1.56-1.83 (m, 3H), 1.31 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 148.5, 147.1, 128.2, 128.2, 126.7, 125.8, 78.0, 64.3, 63.2, 47.4, 27.1, 26.2; HRMS (EI): m/z calcd for C19H22BNO3 323.1693; found: 323.1691

Synthesis of (S)-3-Chloro-1-(2-thienyl)-1-propanol, (S)-4. To stirred solution of (R)-3b (215 mg, 0.66 mmol) in anhydrous THF (20 mL), BH3·SMe2 (634 mg, 8.34 mmol) was added in one portion under nitrogen atmosphere. The resulting mixture was stirred for 15 min until a transparent solution was observed. To this solution, a solution of 1 (2.09 g, 11.9 mmol) in THF (5 mL) was added dropwise for 5 min. The resulting mixture was stirred at room temperature for 1 h, and quenched with MeOH (5 mL). The solvents were removed under reduced pressure and the residue was parti-tioned with EtOAc and water. The aqueous phase was ex-tracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine, dried over Na2SO4, and then evaporated under reduced pressure. The crude was purified by silica gel column chromatography on silica gel (hexane/EtOAc = 3/1) to afford (S)-4 (1.93 g, 92%) as an oil. (c 1.2, MeOH); 1H NMR (300 MHz, CDCl3) δ 7.28 (dd, 1H, J = 4.9, 1.3 Hz), 7.00 (m, 2H), 5.18 (m, 1H), 3.75 (m, 1H), 3.58 (m, 1H), 2.39-2.14 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 147.4, 126.8, 124.9, 124.1, 67.2, 41.5, 41.4; HRMS (EI) m/z calcd for C7H9ClOS 176.0063; found: 176.0041; GC analysis: CP-Chirasil-Dex CB (25 m, 0.25 mm, 0.25 mm), Injector: 280 °C; Oven: 70 °C for 3 min to 210 °C at 10 °C/min hold 3 min, FID: 280 °C; t1 = 69.9 min (R), t2 = 70.3 min (S); ee = 95%.

Synthesis of (S)-3-Iodo-1-(2-thienyl)-1-propanol. A mixture of (S)-4 (390 mg, 2.20 mmol) and a NaI-saturated acetone solution (20 mL) was stirred at reflux overnight in a dark place away from light. The mixture was filtered to remove the precipitated NaCl and the filtrate was concentrat-ed in vacuo. The residue was dissolved in water (20 mL) and extracted with Et2O (3 × 10 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated to yield the corresponding iodide (560 mg) as a yellow oil. This material was used without any further puri-fication.

Synthesis of (S)-3-Methylamino-1-(2-thienyl)-1-pro-panol, (S)-5. To a solution of the previously prepared iodide (560 mg, 2.08 mmol) in THF (5 mL), was added 40% aqueous MeNH2 (2.2 mL, 25.4 mmol). The resulting mixture was stirred at room temperature for 6 h. The reaction mixture was treated with 5 N NaOH (1 mL), and then con-centrated in vacuo. The residue was dissolved in water (20 mL) and extracted with Et2O (3 × 20 mL). The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH = 40:10:1) to afford (S)-5 (267 mg, 71% for two steps) as a clear oil. [α]D25=−12.5 (c 1.2, MeOH); 1H NMR (300 MHz, CDCl3) δ 7.22-7.20 (m, 1H), 6.98-6.91 (m, 2H), 5.21 (ddd, 1H, J = 8.2, 3.2, 0.7 Hz), 3.56 (brs, 2H), 3.01-2.83 (m, 2H), 2.45(s, 3H), 2.04-1.83 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 149.7, 126.5, 123.7, 122.3, 72.1, 50.2, 36.8, 35.9; MS (EI) m/z (%) 171 (M+, 35), 139 (22), 128 (100), 111(31).

Synthesis of (S)-Duloxetine (1). To a solution of (S)-5 (171 mg, 1 mmol) in DMSO (5 mL), were added NaH (36 mg 1.5 mmol) and 1-fluoronaphthalene (190 mg, 1.3 mmol). After stirring for 8 h, the reaction mixture was partitioned with ethyl acetate and water. After an extractive workup, the combined organic layers were dried over sodium sulfate and then concentrated in vacuo. The residue was purified by flash chromatography (CH2Cl2/MeOH/NH4OH = 40:10:1) to yield 1 (232 mg, 78%) as a colorless oil. [α]D25= +110.5 (c 1.1, MeOH); 1H NMR (300 MHz, CDCl3) δ 8.37-8.33 (m, 1H), 7.79-7.74 (m, 1H), 7.50-7.44 (m, 2H), 7.39-7.37 (m, 1H), 7.28-7.18 (m, 2H), 7.05-7.04 (m, 1H), 6.93-6.90 (m, 1H), 6.86-6.84 (m, 1H), 5.78 (dd, 1H, J = 7.6, 5.3 Hz ), 2.86-2.78 (m, 2H), 2.50-2.39 (m, 4H), 2.27-2.16 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 153.3, 145.2, 134.5, 127.4, 126.5, 126.2, 126.1, 125.7, 125.2, 124.6, 124.5, 122.1, 120.5, 106.9, 74.7, 48.3, 39.0, 36.5; MS (EI) m/z (%) 297 (M+, 4), 187 (80), 153 (69), 144 (100); HPLC analysis: (Chiralcel OD-H, hexane/IPA = 85/15, 0.5 mL/min; t1 = 18 min (S), t2 = 25 min (R); ee = 96%.