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A Practical Synthesis of the Antidepressant (S)-Duloxetine
A Practical Synthesis of the Antidepressant (S)-Duloxetine
Bulletin of the Korean Chemical Society. 2014. Jun, 35(6): 1894-1896
Copyright © 2014, Korea Chemical Society
  • Received : January 24, 2014
  • Accepted : February 25, 2014
  • Published : June 20, 2014
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About the Authors
Sun-Ah Lee
Green Chemistry Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Korea
Venkata Subbaiah Sadu
Major of Green Chemistry and Environmental Biotechnology, University of Science & Technology, Daejeon 305-333, Korea
No-Joong Park
Green Chemistry Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Korea
In-Taek Hwang
Green Chemistry Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Korea
Kee-In Lee
Major of Green Chemistry and Environmental Biotechnology, University of Science & Technology, Daejeon 305-333, Korea

Abstract
Keywords
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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 AlCl 3 . 11 Yield: 19.2 g (95%); 1 H NMR (300 MHz, CDCl 3 ) 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;
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( c 0.12, CHCl 3 ); 1 H NMR (300 MHz, DMSO- d 6 ) 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); 13 C NMR (75 MHz, DMSO- d 6 ) 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 C 19 H 22 BNO 3 323.1693; 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), BH 3 ·SMe 2 (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 Na 2 SO 4, 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.
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( c 1.2, MeOH); 1 H NMR (300 MHz, CDCl 3 ) 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); 13 C NMR (75 MHz, CDCl 3 ) δ 147.4, 126.8, 124.9, 124.1, 67.2, 41.5, 41.4; HRMS (EI) m/z calcd for C 7 H 9 ClOS 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; t 1 = 69.9 min ( R ), t 2 = 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 Et 2 O (3 × 10 mL). The combined organic extracts were washed with brine, dried over Na 2 SO 4 , 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 MeNH 2 (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 Et 2 O (3 × 20 mL). The combined extracts were washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo . The residue was purified by flash chromatography on silica gel (CH 2 C l2 /MeOH/NH 4 OH = 40:10:1) to afford ( S )- 5 (267 mg, 71% for two steps) as a clear oil. [α] D 25 =−12.5 ( c 1.2, MeOH); 1 H NMR (300 MHz, CDCl 3 ) 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); 13 C NMR (75 MHz, CDCl 3 ) 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 (CH 2 C l2 /MeOH/NH 4 OH = 40:10:1) to yield 1 (232 mg, 78%) as a colorless oil. [α] D 25 = +110.5 ( c 1.1, MeOH); 1 H NMR (300 MHz, CDCl 3 ) 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); 13 C NMR (75 MHz, CDCl 3 ) 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; t 1 = 18 min ( S ), t 2 = 25 min ( R ); ee = 96%.
Acknowledgements
We thank the INNOPOLIS Founda-tion, Daedeok Branch (KN-1312) and PHARMA GEN Co., Ltd. for supporting this work.
References
Chen Z. , Skolnick P. 2007 Expert Opin. Investig. Drugs 16 1365 -    DOI : 10.1517/13543784.16.9.1365
Bymaster F. P. , Beedle E. E. , Findlay J. , Gallagher P. T. , Krushinski J. H. , Mitchell S. , Robertson D. W. , Thompson D. C. , Wallace L. , Wong D. T. 2003 Bioorg. Med. Chem. Lett. 13 4477 -    DOI : 10.1016/j.bmcl.2003.08.079
Deeter J. , Frazier J. , Staten G. , Staszak M. , Weigel L. 1990 Tetrahedron Lett. 31 7101 -    DOI : 10.1016/S0040-4039(00)97251-4
Zhou J.-N. , Fang Q. , Hu Y.-H. , Yang L.-Y. , Wu F.-F. , Xie L.-J. , Wu J. , Li S. 2014 Org. Biomol. Chem. 12 1009 -    DOI : 10.1039/c3ob42214c
Kamal A. , Malik M. S. , Shaik A. A. , Azeeza S. 2008 Tetrahedron: Asymmetry 19 1078 -    DOI : 10.1016/j.tetasy.2008.03.028
Huskens J. , Goddard R. , Reetz M. T. 1998 J. Am. Chem. Soc. 120 6617 -    DOI : 10.1021/ja980215x
Huskens J. , Reetz M. T. 1999 Eur. J. Org. Chem. 1775 -