Council of Scientific and Industrial Research (India), WO 2015087352, process for the synthesis of aryl sulfones

WO-2015087352
 process for the synthesis of aryl sulfones
The present patent discloses a novel, efficient and transition-metal-free room temperature single step process for synthesis of aryl sulfones and substituted aryl sulfones starting from aryl substrates.

Baburao Mhaske, Santosh; Pandya, Virat

Novel and transition-metal-free, room temperature, single step process for preparing aryl sulfones and substituted aryl sulfones. Aryl sulfones are useful as intermediates in the synthesis of drugs eg rofecoxib and laropiprant; while substituted aryl sulfones possess anticancer and anti-HIV activities. ROFECOXIB LAROPRIPRANT see WO2014024212 (listing Santosh Baburao Mhaske as one of the inventors), claiming a similar one-pot synthesis of aryl phosphorous compounds. Also see Org Lett, Jul 2014, for an article, covering the theme of invention. WO2014024212 http://www.google.com/patents/WO2014024212A1?cl=en Example 1: General Experimental Procedure for the Phosphorylation: To a flame dried two-neck round-bottom flask containing CsF (5.50 equiv.) was added o-silyl aryl triflate (II) (1.00 equiv.) in acetonitrile, followed by addition of phosphorous compound of formula (III) (4.00 equiv.) in acetonitrile under argon atmosphere. The reaction mixture was stirred at room temperature and the progress was monitored by TLC. After completion of the reaction, acetonitrile was removed on rotary evaporator and the crude product was dried under high vacuum and purified by flash silica gel column using a gradient of ethyl acetate-petroleum ether to afford corresponding aryl-phosphorous compounds of formula (I) in good to excellent yields. Example 2: Synthesis of diethyl phenylphosphonate (1) To a stirred solution of CsF (Cesium Fluoride, 1.4 g, 9.22 mmol) in anhydrous acetonitrile (5 mL) was consecutively added o-trimethylsilyl phenyl triflate (500 mg, 1.67 mmol) and triethyl phosphite (1.12 g, 6.71 mmol). Reaction mixture was allowed to stir at room temperature (30 °C) for 20 hrs. The reaction mixture was concentrated and directly loaded on silica gel column and purified by using solvent gradient of Pet. EthenEthyl Acetate (1 : 1) to yield a colourless liquid phosphonate 1 (345 mg, 96%). Reaction Time: 20 h, Rf. 0.4 (1 : 1 EtOAc:Pet. Ether); Thick oil; 345 mg, 96 %; Ή NMR (400 MHz, CDC13, TMS) δ 7.88-7.77 (m, 2H), 7.60-7.52 (m, 1H), 7.51 -7.43 (m, 2H), 4.22-4.02 (m, 4H), 1.33 (t, J= 7.2 Hz, 6H); 13C NMR (100 MHz, CDC13, TMS) δ 132.3 (d, J= 2.3 Hz), 131.7 (d, J= 10.0 Hz), 128.4 (d, J = 14.6 Hz), 128.3 (d, J = 188.0 Hz), 62.0 (d, J= 5.4 Hz), 16.3 (d, J = 6.2 Hz); 31P NMR (162 MHz, CDC13) δ 18.8; Mass (M+Na)+ 237; Known compound, Lit. M. Kalek, A. Ziadi, J. Stawinski, Org. Lett. 2008, 10, 4637. Example 3: Synthesis of dimethyl phenylphosphonate (2) To a stirred solution of CsF (112 mg, 0.74 mmol) in anhydrous acetonitrile was consecutively added o-trimethylsilyl phenyl triflate (40 mg, 0.13 mmol) and trimethyl phosphite (67 mg, 0.53 mmol). Reaction mixture was allowed to stir at room temperature (30 °C) for 16 hrs. The reaction mixture was concentrated and directly loaded on silica gel column and purified by using solvent gradient of Pet. EthenEthyl Acetate (1 : 1) to yield a colourless liquid phosphonate 2 (22 mg, 90%). Reaction Time: 16 h; Rf. 0.4 (1 :1 EtOAc:Pet. Ether); Thick oil; 22.0 mg, 90%; Ή NMR (500 MHz, CDC13, TMS) δ 7.80 (dd, J = 8.2, 13.4 Hz, 2H), 7.60-7.55 (m, 1H), 7.51-7.46 (m, 2H), 3.78 (s, 3H), 3.76 (s, 3H); 1 C NMR (125 MHz, CDC13, TMS) δ 132.6 (d, J= 2.9 Hz), 131.8 (d, J = 9.5 Hz), 128.5 (d, J = 15.3 Hz), 126.9 (d, J = 188.8), 52.6 (d, J = 5.7 Hz); 3,P NMR (162 MHz, CDCI3) δ 21.7; Mass (M + Na)+ 209; Known compound, Lit. M. Kalek, A. Ziadi, J. Stawinski, Org. Lett. 2008, 10, 4637. Example 4: Dibutyl phenylphosphonate (3) 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (25 mg, 0.083 mmol), Cesium Fluoride (70 mg, 0.461 mmol), Tributyl phosphite (83 mg, 0.335 mmol), Acetonitrile (1 ml): Reaction Time: 24 h; Rf. 0.4 (1:3 EtOAc:Pet. Ether); Thick oil; 16.3 mg, 72 %; Ή NMR (400 MHz, CDC13, TMS) δ 7.80 (dd, 7= 6.8, 13.3 Hz, 2H), 7.55 (t, J= 7.5 Hz, 1H), 7.50-7.42 (m, 2H), 4.12-3.95 (m, 4H), 1.65 (quint, J = 7.3 Hz, 4H), 1.39 (sext, J = 7.3 Hz, 4H), 0.9 (t, J = 7.3 Hz, 6H); 13C NMR (100 MHz, CDCl3, TMS) 6 132.3 (d, J= 3.1 Hz), 131.7 (d, J= 9.3 Hz), 128.4 (d, J = 15.4 Hz), 128.3 (d, J = 187.3 Hz), 65.8 (d, J = 5.4 Hz), 32.4 (d, J = 6.9 Hz), 18.7, 13.6; 31P NMR (162 MHz, CDCI3) δ 18.8; Mass (M + Na)+ 293; Known compound, Lit. X. Lu, J. Zhu, Synthesis 1987, 8, 726. Example 5: Diethyl 2,5-dimethylphenylphosphonate (4): 3,6-dimethyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (25mg, 0.076 mmol), Cesium Fluoride (64 mg, 0.421 mmol), Triethtyl phosphite (50 mg, 0.306 mmol), Acetonitrile (1 ml): Reaction Time: 35 h; Rf. 0.3 (1 :4 EtOAc:Pet Ether); Thick oil; 16.1 mg, 87 % ; Ή NMR (400 MHz, CDC13, TMS) δ 7.75 (d, J = 14.8, 1 H), 7.23 (d, J = 7.8 Hz, 1 H), 7.17-7.10 (m, 1H), 4.21-4.00 (m, 4H), 2.52 (s, 3H), 2.34 (s, 3H), 1.33 (t, J = 7.3 Hz, 6H); 13C NMR (100 MHz, CDCI3, TMS) 8 138.5 (d, J = 10.0 Hz), 134.9 (d, J = 14.6 Hz), 134.5 (d, J = 10.8 Hz), 133.2, 131.1 (d, 7 = 15.4 Hz), 126.3 (d, J = 182.7 Hz), 61.8 (d, J = 5.4 Hz), 20.7, 20.6, 16.3 (d, = 6.2 Hz); 31P NMR (162 MHz, CDC13) 6 20.0; Mass (M + Na)+ 265; Known Compound, Lit. S. Branion, V. Benin, Synth.Commun. 2006, 36, 2121. Example 6: Diethyl 3-methoxyphenylphosphonate (5): 3-methoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (25 mg, 0.076 mmol), Cesium Fluoride (63 mg, 0.419 mmol), Triethtyl phosphite (50 mg, 0.304 mmol), Acetonitrile (1 ml): Reaction Time: 24 h; Rf. 0.3 (2:3 EtOAc:Pet Ether); Thick oil; 13.7 mg, 74 %; Ή NMR (200 MHz, CDCI3, TMS) δ 7.45-7.28 (m, 3H), 7.15-7.01 (m, 1H), 4.25-3.96 (m, 4H), 3.85 (s, 3H), I .33 (t, J = 7.1 Hz, 6H); 13C NMR (100 MHz, CDC13, TMS) δ 159.4 (d, J= 18.5 Hz), 129.7 (d, J = 17.7 Hz), 129.6 (d, J= 187.3 Hz), 124.0 (d, J = 9.3 Hz), 1 18.8 (d, 7= 3.1 Hz), 1 16.4 (d, J = I I .6 Hz), 62.2 (d, J = 5.4 Hz), 55.41, 16.3 (d, J = 6.2 Hz); 31P NMR (162 MHz, CDC13) δ 18.7; Mass (M + Na)+ 267; Known Compound, Lit. G. Yang, C. Shen, L. Zhang, W. Zhang. Tetrahedron Lett. 2011, 52, 5032. Example 7: Diethyl benzo[d] [l,3]dioxol-5-ylphosph0nate (6): 6-(trimethylsilyl)benzo[d][l,3]dioxol-5-yl trifluoromethanesulfonate (25 mg, 0.073 mmol), Cesium Fluoride (61 mg, 0.402 mmol), Triethtyl phosphite (48 mg, 0.292 mmol), Acetonitrile (1 ml): Reaction Time: 16 h; Rf. 0.3 (2:3 EtOAc:Pet Ether); Thick oil; 16.0 mg, 85 %; Ή NMR (500 MHz, CDCI3, TMS) δ 7.38 (dd, J = 7.9, 14.0 Hz, 1H), 7.20 (d, J = 12.8 Hz, 1H), 6.88 (dd, J = 3.4, 7.6 Hz, 1H), 6.03 (s, 2H), 4.17-4.01 (m, 4H), 1.32 (t, J = 7.0 Hz, 6H); , C NMR (100 MHz, CDC13) TMS) 5151.2 (d, J = 2.9 Hz), 147.8 (d, J= 22.9 Hz), 127.4 ( d, J= 11.4 Hz), 121.3 (d,J= 193.6 Hz), 111.2 (d,/= 12.4Hz), 108.6 (d,J= 18.1 Hz), 101.5, 62.0 (d,J=5.7 Hz), 16.3 (d, J= 6.7 Hz); 3IP NMR (162 MHz, CDC13) δ 19.0 ; Mass (M + Na)+ 281; Known Compound, Lit. G. Yang, C. Shen, L. Zhang, W. Zhang. Tetrahedron Lett.2011, 52, 5032. Example 8: Diethyl 3,4-difluorophenylphosphonate (7): 4,5-difluoro-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (25 mg, 0.078 mmol), Cesium Fluoride (62 mg, 0.411 mmol), Triethtyl phosphite (50 mg, 0.299 mmol), Acetonitrile (1 ml): Reaction Time 4 h; Rf: 0.5 (2:3 EtOAc:Pet Ether); Thick oil; 14.6 mg, 78 %; Ή NMR (500 MHz, CDC13> TMS) δ 7.67-7.55 (m, 2H), 7.31-7.23 (m, 1H), 4.21-4.05 (m, 4H), 1.34 (t, J= 7.0 Hz, 6H); 13C NMR (125 MHz, CDC13, TMS) 6153.1 (ddd, J= 3.8, 12.4, 255.6 Hz), 150.2 (ddd, J= 13.4, 22.9, 252.7 Hz), 128.8 (ddd, J= 3.8, 6.7, 10.5 Hz) 125.9 (dt, J= 3.8, 192.7 Hz), 121.1 (dd,J= 11.4, 18.1 Hz), 117.9 (t,J= 18.1 Hz), 62.4 (d, J= 4.8 Hz), 16.2 (d, J= 5.7 Hz) 3,P NMR (162 MHz, CDC13) δ 15.8 (apparent t, JPF = 6.1 Hz); HRMS-ESI (m/z) calcd (CioH,3F203P + H)+: 251.0643 found: 251.0643. Example 9: Dimethyl 3,4-difluorophenylphosphonate (8): O F^^P(OMe)2 4,5-difluoro-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (25 mg, 0.074 mmol), Cesium Fluoride (62 mg, 0.411 mmol), Trimethtyl phosphite (37 mg, 0.299 mmol), Acetonitrile (1 ml): Reaction Time: 4 h; Rf.0.4 (1:3 EtOAc:Pet Ether); Thick oil; 11.8 mg, 71 %; Ή NMR (400 MHz, CDC13, TMS) S 7.67-7.53 (m, 2H), 7.34-7.24 (m, 1H), 3.79 (s, 3H), 3.77 (s, 3H); 13C NMR (100 MHz, CDC13, TMS) δ 153.3 (ddd, J = 3.9, 12.3, 256.6 Hz), 150.3 (ddd, J= 12.3, 22.4, 252.0 Hz), 129.0 (ddd, J= 3.9, 6.9, 10.8 Hz), 124.2 (dt,J=3.9, 193.4 Hz), 121.3 (dd,J = 11.6, /= 18.5 Hz), 118.0 (t, J= 17.7 Hz), 52,9 (d, J= 6.2 Hz);31P NMR (162 MHz, CDC13) δ 18.6 (d, JpF = 7.5 Hz); HRMS-ESI (m/z) calcd (C8H9F203P + H)+: 223.0330 found: 223.0335. Example 10: Diethyl naphthalen-2-ylphosphonate (9): l-(trimethylsilyl)naphthalen-2-yl trifluofomethanesulfonate (25 mg, 0.073 mmol), Cesium Fluoride (60 mg, 0.395 mmol), Triethtyl phosphite (47 mg, 0.287 mmol), Acetonitrile (1 ml): Reaction Time 24 h; Rf: 0.3 (1 :3 EtOAc:Pet. Ether); Thick oil; 15.5 mg, 82 %; Ή NMR (400 MHz, CDC13, TMS) δ 8.44 (d, J = 15.6 Hz, 1H), 7.97-7.85 (m, 3H), 7.81-7.72 (m, 1H), 7.64- 7.52 (m, 2H), 4.26-4.05 (m, 4H), 1.34 (t, J= 7.0 Hz, 6H); 13C NMR (100 MHz, CDC13, TMS) δ 135.0 (d, J = 2.3 Hz), 134.0 (d, /= 10.0 Hz), 132.3 (d, J = 16.2 Hz), 128.9, 128.3 (d, J = 14.7 Hz), 128.2, 127.8, 126.8, 126.4 (d, J = 9.2 Hz), 125.3 (d, J = 188.1 Hz), 62.1 (d, J = 5.4 Hz), 16.3 (d, J = 6.2 Hz); 31P NMR (162 MHz, CDC13) δ 19.1 ; Mass (M + Na)+ 287; Known compound, Lit. M. Kalek, A. Ziadi, J. Stawinski, Org. Lett. 2008, 10, 4637. Example 11: Synthesis of ethyl diphenylphosphinate (10) To a stirred solution of CsF (70 mg, 0.46 mmol) in anhydrous acetonitrile (1 mL) was consecutively added o-trimethylsilyl phenyl inflate (25 mg, 0.08 mmol) and diethyl phenyl phosphonite (66 mg, 0.33 mmol). Reaction mixture was allowed to stir at room temperature (30 °C) for 24 hrs. The reaction mixture was concentrated and directly loaded on silica gel column and purified by using solvent gradient of Pet. EthenEthyl Acetate (1 : 1) to yield a colourless liquid phosphinate (15.7 mg, 76%). Reaction Time: 24 h; Rf: 0.3 (1 : 1 EtOAc:Pet Ether); Thick oil; 15.7 mg, 76 %; Ή NMR (400 MHz, CDC13) TMS) δ 7.87-7.77 (m, 4H), 7.55-7.48 (m, 2H), 7.47-7.39 (m, 4H), 4.1 1 (apparent quint, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H); 13C NMR ( 100 MHz, CDC13, TMS) 5 132.0 (d, J = 2.1 Hz), 131.6 (d, J = 136.4 Hz), 131.5 (d, J = 10.1 Hz), 128.4 (d, J = 13.1 Hz ), 61.1 (d, J = 5.4 Hz), 16.4 (d, J = 6.2 Hz); 31 P NMR (162 MHz, CDC13) 8 31.3; HRMS-ESI (m/z) calcd (CMH,502P + H)+ : 247.0882 found: 247.0886; Known compound, Lit. C. Huang, X. Tang, H. Fu, Y. Jiang, Y. Zhao, J. Org. Chem. 2006, 71, 5020. Example 12: Ethyl (2,5-dimethylphenyl)(phenyl)phosphinate (11): 3,6-dimethyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (25 mg, 0.077 mmol), Cesium Fluoride (64 mg, 0.421 mmol), Diethyl phenylphosphonite (60 mg, 0.306 mmol), Acetonitrile (1 ml): Reaction Time: 32 h; Rf. 0.4 (1 : 1 EtOAc:Pet Ether); Thick oil; 13.0 mg, 62 %; Ή NMR (400 MHz, CDC13, TMS) δ 7.81 -7.70 (m, 3H), 7.52-7.40 (m, 3H), 7.23 (d, J = 7.8 Hz, 1H), 7.12-7.05 (m, 1H), 4.11 (apparent quint, J = 7.0 Hz, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 1.38 (t, J = 7.0 Hz, 3H); ,3C NMR (100 MHz, CDC13, TMS) 5 138.6 (d, J = 10.8 Hz), 135.0 (d, J = 12.3 Hz), 133.9 (d, J = 9.3 Hz), 132.5 (d, J = 124.1 Hz), 128.4 (d, J = 13.4 Hz ), 131.7, 131.5 (d, J = 7.7 Hz), 131.4, 131.3, 129.0 (d, J = 133.3 Hz), 128.4 (d, J = 13.1Hz), 60.7 (d, J= 5.4 Hz), 20.9, 20.7 (d, J = 3.9 Hz), 16.4 (d, J = 6.9 Hz); 3 IP NMR (162 MHz, CDC13,) δ 32.2; HRMS-ESI (m/z) calcd (β,6Η,9θ2Ρ + H)+ : 275.1 195 found: 275.1 193. Example 13: (2,5-dimethylphenyl)diphenylphosphine oxide (12) To a stirred solution of CsF (63 mg, 0.42 mmol) in anhydrous acetonitrile 1 mL was consecutively added 2,5 dimethyl -(o-trimethyl silyl)phenyl triflate (25 mg, 0.077 mmol) and ethoxydiphenylphosphine (60 mg, 0.31 mmol). Reaction mixture was allowed to stir at room temperature (30 °C) for 30 hrs. The reaction mixture' was concentrated and directly loaded on silica gel column and purified by using solvent gradient of Pet. EthenEthyl Acetate (1 : 1) to yield a white solid phosphine oxide (19 mg, 81%). Reaction Time: 30 h; Rf: 0.3 (1 : 1 EtOAc:Pet Ether); White Solid; mp 157-159 °C; 19.0 mg, 81 %; 1 H NMR (400 MHz, GDC13, TMS) δ 7.75-7.60 (m, 4H), 7.59-7.52 (m, 2H), 7.51-7.43 (m, 4H), 7.26-7.20 (m, 1H), 7.19-7.13 (m, 1H), 6.88 (d, J = 14.4 Hz, 1H), 2.37 (s, 3H), 2.21 (s, 3H); 13C NMR ( 100 MHz, CDCI3, TMS) 5 140.0 (d, J = 7.7 Hz), 134.7 (d, J = 13.1 Hz), 133.9 (d, J = 12.3 Hz), 132.9 (d, J = 103.3 Hz), 132.8 (d, J = 2.3 Hz), 13Ί .9 (d, J = 10.0 Hz), 131.8, 131.7 (d, J = 3.1 Hz), 130.4(d, J= 103.3 Hz), .128.5 (d, J = 11.6 Hz), 21.2 (d, J = 4.6 Hz), 21.0; 31P NMR ( 162 MHz, CDCI3) δ 31.7; HRMS-ESI (m/z) calcd (C20H19OP + H)+ : 307.1246 found: 307.1244. Example 14: Synthesis of (3-methoxyphenyl)diphenylphosphine oxide (13) To a stirred solution of CsF (64 mg, 0.42 mmol) in anhydrous acetonitrile was consecutively added 2-methoxy (o-trimethyl silyl) phenyl triflate (25 mg, 0.077 mmol) and ethoxydiphenylphosphine (61 mg, 0.31 mmol). Reaction mixture was allowed to stir at room temperature (30 °C) for 20 hrs. The reaction mixture was concentrated and directly loaded on silica gel column and purified by using solvent gradient of Pet. EthenEthyl Acetate (1 : 1) to yield a white sticky solid phosphine oxide (16 mg, 68%). Reaction Time: 20 h; Rf. 0.3 (1 : 1 EtOAc:Pet Ether); Thick oil; 16.0 mg, 68 %; Ή NMR (400 MHz, CDC13, TMS) δ 7.71-7.63 (m, 4H), 7.59-7.52 (m, 2H), 7.50-7.43 (m, 4H), 7.40-7.29 (m, 2H), 7.18-7.05 (m, 2H), 3.80 (s, 3H); 13C NMR (100 MHz, CDC13, TMS) δ 159.6 (d, / = 15.4 Hz), 133.8 (d, 7 = 103.3 Hz), 132.4 (d, J = 104.0 Hz), 132.1 (d, J = 10.0 Hz), 131.9 (d, J = 3.1 Hz), 129.6 (d, J= 14.6 Hz), 128.5 (d, J= 12.3 Hz), 124.4 (d, J= 10.0 Hz), 1 18.2 (d, J= 3.1 Hz), 1 16.7 (d, J = 10.8 Hz), 55.4; 31P NMR (162 MHz, CDC13) δ 29.5; HRMS-ESI (m/z) calcd (C19Hi702P + H)+ : 309.1039 found: 309.1034; Known compound, Lit. X. Zhang, H. Liu, X. Hu, G. Tang, J. Zhu, Y. Zhao, Org. Lett. 2011, 13, 3478. Example 15: Triphenylphosphine oxide (14): 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (25 mg, 0.083 mmol), Cesium Fluoride (70 mg, 0.461 mmol), Ethoxydiphenylphosphane (78 mg, 0.33 mmol), Acetonitrile (1 ml): Reaction Time: 16 h; Rf: 0.3 (1 :3 EtOAc:Pet Ether); White Solid; 17.5 mg, 75 %; Ή NMR (400 MHz, CDC13, TMS) δ 7.74-7.63 (m, 6H), 7.59-7.51 (m, 3H), 7.50-7.40 (m, 6H);13C NMR (100 MHz, CDCI3, TMS) δ 132.5 (d, J = 104.0 Hz), 132.1 (d, J = 10.0 Hz), 131.9 (d, J= 2.3 Hz); 128.5 (d, J = 12.4 Hz); 31P NMR (162 MHz, CDC13) δ 29.2; Mass (M + Na)+ 301; Known Compound, Lit. K. Prokop, D. Goldberg, J. Am. Chem. Soc. 2012, 134, 8014. Example 16: Naphthalen-2-yldiphenylphosphine oxide (15): l-(trimethylsilyl)naphthalen-2-yl trifluoromethanesulfonate (25 mg, 0.071 mmol), Cesium Fluoride (60 mg, 0.395 mmol), Ethoxydiphenylphosphane (68 mg, 0.287 mmol), Acetonitrile (1 ml): Reaction Time: 16 h; Rf. 0.4 (1 :3 EtOAc:Pet Ether); Thick oil; 19.5 mg, 83 %; Ή NMR (400 MHz, CDCI3, TMS) δ 8.28 ( d, J = 13.8 Hz, 1H), 7.95-7.84 (m, 3H), 7.79-7.40 (m, 13 H); 13C NMR (100 MHz, CDC13, TMS) δ 134.7 (d, J= 2.3 Hz), 134.0 (d, J= 9.3 Hz), 133.0, 132.3, 132.1 (d, J =10.0 Hz), 132.0 (d, J = 1.5 Hz), 131.3 (d, 7 = 243.5 Hz), 128.9, 128.5 (d, J = 12.3 Hz), 128.4, 128.2, 127.4 (d, J = 87.9 Hz), 126.8 (d, J= 10.8 Hz); 3IP NMR (162 MHz, CDC13) δ 29.3; HRMS-ESI (m/z) calcd (C22H17OP + H)+ : 329.1090 found: 329.1086; Known compound, Lit. Y.-L. Zhao, G.-J. Wu, Y. Li, L.-X. Gao, F.-S. Han, Chem. Eur. J. 2012, 18, 9622. ADVANTAGES OF THE INVENTION 1. Raw materials are commercially available and inexpensive 2. One pot process 3. Room temperature process 4. The process is useful in generating chiral phosphine oxides under mild conditions that can serve as precursors to obtain novel aryl-phosphine ligands useful in organic synthesis. .

Novel process for preparing (+)-cis-sertraline WO 2001068566

Novel process for preparing (+)-cis-sertraline  WO 2001068566 

http://www.google.com/patents/WO2001068566A1?cl=en

The methods of the present invention for making (+)-cis-sertraline allow sertraline-precipitant, or sertraline-mandelate, to be made directly from the sertraline racemate resulting from the hydrogenation, reduction, of the sertraline- 1-imine. This improved, efficient and cost effective purification is possible when the sertraline racemate has a relatively high cis/trans ratio, such as, about 8:1 to about 12:1, as well as when the content of dechlorinated-sertraline side products is low, such as, less than about 1%. The methods of the present invention successfully eliminate the need for several purification steps prior to selectively precipitating (+)-cis-sertraline with an optically active selective precipitant.

Sertraline hydrochloride, (lS-cis)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N- methyl-1-naphthalenamine hydrochloride, having the formula

Sertraline hydrochloride

is the active ingredient in Zoloft®, a medication approved by the U.S. Food and Drug Administration, for the treatment of depression, obsessive-compulsive disorder and panic disorder.

Sertralone

U.S. Patent No. 4,536,518 describes a synthesis of sertraline hydrochloride from sertralone. The process for synthesizing sertraline hydrochloride from sertralone comprises two steps. First, sertralone is condensed with methyl amine in the presence of an acid catalyst, to yield the Schiff base of sertralone, sertraline- 1-imine.

Sertraline 1-imine

The imine, or Schiff base, is then reduced to sertraline. The reduction process of U.S. Patent No. 4,536,518 comprises the hydrogenation of sertraline- 1-imine concentrate at room temperature for two hours over 10% Pd/C catalyst in an atmosphere of hydrogen (1 atm pressure). The product is a racemic mixture of the cis and trans diastereomers ("(±)- cis/trans-sertraline") in the ratio of approximately 3 to 1. This hydrogenation step can introduce a number of contaminants, including dechlorinated side-products, if not carefully controlled. One very problematic group of side products are dechlorinated- sertraline derivatives. It is desirable to have a hydrogenation method that reduces the amount of dechlorinated-sertraline side products or eliminates these side products.

The purification of cis-sertraline from (±)-cis/trans-sertraline as described in the '518 patent is relatively complicated and expensive requiring multiple recrystallizations, and the (±)-cis/trans-sertraline so produced has a cis/trans ratios lower than 3:1. It is therefore desirable to have a method of initially making cis/trans-sertraline base from sertraline- 1-imine with cis/trans ratios greater than 3:1. It is also desirable to have a simple and cost effective purification of (+)-cis-sertraline from (±)-cis/trans-sertraline base or from (±)-cis/trans-sertraline hydrochloride.

EXAMPLES

EXAMPLE 1 Step 1: Preparation of sertraline- 1-imine (Schiff base):

Sertralone (100 g) was dissolved in toluene (1400 mL) and the solution so obtained was cooled to 0-5 °C. Methyl amine gas (38.7 g) was bubbled through the solution while maintaining the temperature between 0-5 °C. To the above solution, TiCl₄(20 mL) was added dropwise while maintaining the temperature below 10°C. The reaction mixture was allowed to warm to room temperature and then was stirred at room temperature for 3 hours. Upon completion of the reaction, TiO₂ was removed by filtration and the filtrate was evaporated to dryness. The solid obtained after evaporation was sertraline- 1-imine (101.17 g; yield 100%).

Step 2: Preparation of (drVcis/trans-sertraline (sertraline racemate) free base:

A slurry of sertraline- 1-imine (Schiff base) (10 g) in t-butyl-methyl-ether (MTBE) (270 mL) was hydrogenated in the presence of Pd/C (10% loading) at 40 °C, at 1 atm H₂ pressure. After approximately 5 hours the reaction was complete. Filtration of the reaction mixture through a cellite pad and evaporation of the solvent afforded (±)- cis/trans-sertraline free base (sertraline racemate free base) (10 g) as an oil.

Step 3: Preparation of crude f+)-sertraline mandelate:

Sertraline racemate free base (75.6 g) was dissolved in ethanol (760 mL) and the solution heated to about 50°C. (D)-Mandelic acid (37.6 g) was added and the solution was heated to reflux. The mixture was cooled to room temperature and stirred for 3 hours. Filtration and washing with ethanol followed by drying at about 60 °C afforded the product crude (+)-sertraline mandelate, in 83.7% yield (40.7g), 94.6% SS-sertraline, 3.01% RR-sertraline.

The optical purity of the (+)-sertraline mandelate was established by chiral HPLC.

Step 4: Preparation of (+)-sertraline mandelate crystals

Crude (+)-sertraline mandelate (40 g) was crystallized from ethanol (920 mL). The hot solution was treated with active carbon, filtrated and cooled to room temperature. The obtained solid was isolated by filtration and washed with ethanol. After drying, the (+)-sertraline-mandelate crystals are obtained in 82.8 % yield (31.95 g) 99.0% SS- sertraline by area, no i-R-sertraline was detected.

Step 5: Preparation of (+ -sertraline hydrochloride Form N:

The crude (+)-sertraline mandelate crystals in toluene were partitioned between a 10% aqueous solution of ΝaOH and toluene. The organic solution was washed with water and the solvent was evaporated to dryness to give (+)-sertraline base (6.9 g). The solution of (+)-sertraline base (3.7 g) in ethanol (18.5 mL) was acidified with hydrogen chloride gas while keeping the temperature at about 10°C. Then the mixture was cooled to room temperature and stirred for 2 hours. After filtration, washing of the solid with ethanol and drying, (+)-sertraline hydrogen chloride ((+)-sertraline HCl) Form N was obtained (3.16 g, yield 82.7%>), 99.6% SS-sertraline by area, no i-i?-sertraline was detected.

The procedure of steps 3-5 was performed 5 times as described above. Table 2 includes the specific conditions and results of these 5 experiments.

Table 2.

EXAMPLE 2: OPTICAL RESOLUTION (±)-Sertraline hydrochloride (5 g) was dissolved in ethanol (20 mL) and KOH powder (85%>) was added to the solution. The slurry was stirred at room temperature for 2.5 hrs. After stirring the solids were removed by filtration and the solution was treated with D-(-)-mandelic acid (2.66 g). Precipitation occurred and the stirring was continued for 24 hours. (+)-Sertraline-mandelate was isolated by filtration and washed with ethanol and then dried to yield 2.70 g of (+)-sertraline-mandelate.

Optical purity of (+)-sertraline-mandelate was established by chiral HPLC methods. Table 3 provides additional data and reaction conditions concerning the optical resolution of sertraline. In Table 3, the % Enantiomer RR is the percent area of the RR- enantiomer as determined by chiral HPLC; Chiracel OD-H, 250 x 4.6 nm, 5μ, column temperature 5°C. In Table 3, the Yield %> is the yield of optical resolution, based on the % SS-enantiomer of sertraline hydrochloride practically obtained against the theoretical SS-sertraline hydrochloride enantiomer that could be obtained. The yield was calculated based on the optical purity of (±)-sertraline hydrochloride obtained. In Table 3, the Assay % is the percent of SS-sertraline hydrochloride as determined by chiral HPLC method using SS-sertraline hydrochloride as the standard.

Although certain presently preferred embodiments of the invention have been described herein, it will be apparent to those skilled in the art to which the invention pertains that variations and modifications of the described embodiments may be made without departing from the spirit and scope of the invention. Accordingly, it is intended that the invention be limited only to the extent required by the appended claims and the applicable rules of law.

PATENT CITATIONS

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US5463126 *	Jul 3, 1992	Oct 31, 1995	Pfizer Inc.	Process for preparing sertraline

Reference
1	*	See also references of EP1268369A1

Citing Patent	Filing date	Publication date	Applicant	Title
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WO2005023752A2 *	Sep 7, 2004	Mar 17, 2005	Ben-Zion Dolitzky	A recycling process for preparing sertraline
WO2005121074A2 *	Jun 9, 2005	Dec 22, 2005	Keshav Deo	Processes for the preparation of sertraline hydrochloride
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US6723878	Jun 14, 2002	Apr 20, 2004	Orion Corporation Fermion	Method for preparing sertraline
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US 7326794, Process for the Preparation of High Purity Perindopril and Intermediates Used in its Synthesis

US 7326794

http://www.google.com/patents/US7326794

Process for the Preparation of High Purity Perindopril and Intermediates Used in its Synthesis

Les Laboratoires Servier, Courbevoie Cedex, France

Perindopril 3 is used in treating cardiovascular problems, and other related patents from this company on this compound were reviewed recently (Org. Process Res. Dev. 2008, 12, 146). This patent extends the work covered in the earlier patents and involves the same route that is shown in Reaction 1.

Reaction 1

The process involves acylation of 1a to give 1b that is activated using SOCl2 to form 1c, and this is coupled with 2 to form 3 that is isolated by formation of the tert-butyl salt in 45% yield. The main claim of this patent specifically mentions the synthesis of 3 or the salt that is free from contamination by the benzyl esters 4a and 4b. These compounds are present when DCC is used as a coupling reagent in the alternative synthesis from 1c and the Ts salt of the benzyl ester of 2 Benzyl Esters.The patent also describes the synthesis of the methyl and ethyl analogues of 1b and 1c (R1 = OMe or OEt) from the corresponding chloroformates and Et3N is used in place of K2CO3 in step (a). The But analogue is formed by using (BOC)2O in place of the chloroformates and K2CO3. All of these compounds are novel, and basic 1H NMR data are given for them.

Preparation of Perindopril Eburmine

Example 5 Acylation of perhydroindole-2-carboxylic acid using N-[2-(ethoxycarbonyl)butyl]-N-ethoxycarbonylalanine

To a solution of N-[2-(ethoxycarbonyl)butyl]-N-ethoxycarbonylalanine (10.1 g, 35 mmol) in dichloromethane (35 mL) thionyl chloride (4.2 mL, 6.9 g, 58 mmol) was added in drops at 0-5° C. It was stirred at ambient temperature for 2-3 h. The solvent was evaporated to give a reddish oil. The residue was dissolved in THF (37.5 mL) and it was added to a suspension of perhydroindole-2-carboxylic acid (4.7 g, 28 mmol) in THF (37.5 mL). The suspension was refluxed with stirring for 4-4.5 h until a brownish solution was formed. After evaporation of the solvent the residue was dissolved in ethyl acetate (120 mL), t-butylamine (2.8 mL, 1.95 g, 27 mmol) in ethyl acetate (60 mL) was added slowly to the stirred solution resulting in separation of a crystalline mass. The mixture was heated until a solution was formed, then treated with charcoal. The crystalline product obtained after cooling was filtered to give perindopril eburmine (6.8 g, 55%).

Example 6 Acylation of perhydroindole-2-carboxylic acid using N-[2-(ethoxycarbonyl)butyl]-N-methoxycarbonylalanine

Perindopril eburmine was prepared analogously to Example 5, using N-[2-(ethoxycarbonyl)butyl]-N-methoxycarbonylalanine (3.4 g, 12.5 mmol) and perhydroindole-2-carboxylic acid (1.7 g, 10 mmol). The crystalline product obtained was filtered to give perindopril eburmine (2.4 g, 54%).

Example 7 Acylation of perhydroindole-2-carboxylic Acid Using N-[2-(ethoxycarbonyl)butyl]-N-t-buthoxycarbonylalanine

Perindopril eburmine was prepared analogously to Example 5, using N-[2-5 (ethoxycarbonyl)butyl]-N-t-buthoxycarbonylalanine (0.69 g, 2.2 mmol) and perhydroindole-2-carboxylic acid (0.29 g, 1.7 mmol). The crystalline product obtained was filtered to give perindopril eburmine (0.37 g, 49%).

Example 8 Acylation of perhydroindole-2-carboxylic acid using N-[2-(ethoxycarbonyl)butyl]-N-benzyloxycarbonylalanine

Perindopril eburmine was prepared analogously to Example 5, using N-[2-(ethoxycarbonyl)butyl]-N-benzyloxycarbonylalanine (1.41 g, 4 mmol) and perhydroindole-2-carboxylic acid (0.51 g, 3 mmol). The crystalline product obtained was filtered to give perindopril eburmine (0.60 g, 45%).

Example 9 Acylation of perhydroindole-2-carboxylic acid using N-[2-(ethoxycarbonyl)butyl]-N-ethoxycarbonylalanine

To a solution of N-[2-(ethoxycarbonyl)butyl]-N-ethoxycarbonylalanine (1.45 g, 5 mmol) in dichloromethane (7.5 mL) thionyl chloride (0.6 mL, 0.98 g, 8.5 mmol) was added dropwise at 0-5° C. It was stirred at ambient temperature for 2-3 h. The excess of thionyl chloride and the sulphur dioxide and hydrogen chloride formed was eliminated in slight vacuo. To the dichloromethane solution thus obtained was added perhydroindole-2-carboxylic acid (0.71 g, 4.2 mmol) and dichloromethane (5.0 mL). The suspension was refluxed with stirring for 2 h until a brownish solution was formed. After evaporation of the solvent the residue was dissolved in ethyl acetate (20 mL), whereupon t-butylamine (0.42 mL, 0.29 g, 4.05 mmol) in ethyl acetate (5.0 mL) was added slowly to the stirred solution resulting in separation of a crystalline mass. The mixture was heated until a solution was formed, then treated with charcoal. The crystalline product obtained after cooling was filtered to give perindopril eburmine (0.64 g, 35%).

Cited Patent	Filing date	Publication date	Applicant	Title
US4914214 *	Sep 16, 1988	Apr 3, 1990	Adir Et Cie	Process for the industrial synthesis of perindopril
US6835843	Apr 5, 2001	Dec 28, 2004	Les Laboratoires Servier	Method for synthesis of perindopril and its pharmaceutically acceptable salts
US7060842	Jul 23, 2002	Jun 13, 2006	Les Laboratoires Servier	Method for synthesis of (2S, 3aS, 7aS)-1-{(S)-alanyl}-octahydro-1H -indole-2-carboxylic acid derivatives and use for synthesis of perindopril
US20040248814	Jul 23, 2002	Dec 9, 2004	Pau Cid	Process for the preparation of perindopril, its analgous compounds and salts therof using 2,5 dioxo-oxazolidine intermediate compounds
DE19721290A1	May 21, 1997	Dec 11, 1997	Krka Tovarna Zdravil D D	ACE-inhibiting substituted alanyl-derivatives of e.g. proline preparation
EP0308341A1	Sep 16, 1988	Mar 22, 1989	Adir Et Compagnie	Process for the industrial synthesis of perindopril and for its principal synthesis intermediates
EP1256590A1	Jul 23, 2002	Nov 13, 2002	Les Laboratoires Servier S.A.	Method for synthesis of (2S,3aS,7aS)-1-(S)-alanyl-octahydro-1H-indole-2- carboxylic acid derivatives and use in the synthesis of perindopril
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