India rejects patent on Pfizer's arthritis drug

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Mumbai: India has again denied Pfizer Inc a patent on its rheumatoid arthritis drug tofacitinib, the latest setback for a multinational drugmaker seeking to enforce its intellectual property rights in the country.

Representational image. AFP

Pfizer sought a patent that covers an important chemical formulation of the active compound in the medicine, but the Indian Patent Office said the company would have to establish that the compound for which it is seeking a patent is therapeutically more effective than the active compound.

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. .

BIOCON PATENT..........US20140288269) PROCESS FOR THE PREPARATION OF RANDOM POLYPEPTIDES AND EMPLOYING CIRCULAR DICHROISM AS A GUIDANCE TOOL FOR THE MANUFACTURE OF GLATIRAMER ACETATE .

PROCESS FOR THE PREPARATION OF RANDOM POLYPEPTIDES AND EMPLOYING CIRCULAR DICHROISM AS A GUIDANCE TOOL FOR THE MANUFACTURE OF GLATIRAMER ACETATE (Fri, 26 Sep 2014) 
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BANGALORE: Biotech major Biocon today said its Chairperson and Managing Director Kiran Mazumdar-Shaw

Application Number: 14355504 Application Date: 26.10.2012

Publication Number: 20140288269 Publication Date: 25.09.2014

Publication Kind : A1

PCT Reference: Application Number:PCT/IN2012/000708 ; Publication Number: Click to see the data

IPC: C07K 1/04 C07K 1/14 Applicants: Biocon Limited Inventors: Venkata Srinivas Pullela Khedkar Anand Patil Nitin Sopanrao Ujire Sandhya Chatterjee Amarnath Janakiraman Ashwini Priority Data: 3781/CHE/2011 03.11.2011 IN Title: (EN) PROCESS FOR THE PREPARATION OF RANDOM POLYPEPTIDES AND EMPLOYING CIRCULAR DICHROISM AS A GUIDANCE TOOL FOR THE MANUFACTURE OF GLATIRAMER ACETATE Abstract: (EN) The present invention discloses novel process for the preparation of mixture of polypeptides comprising L-Glutamaic acid, L-Alanine, L-Tyrosine, and L-Lysine. by employing circular dichroism as a guidance tool.

Glatiramer is a peptide based polymer composed of four amino acids: L-Glutamaic acid, L-Alanine, L-Tyrosine, and L-Lysine. It's pharmaceutically acceptable salt Glatiramer acetate is approved by FDA and marketed as Copaxone® for the treatment of multiple sclerosis. Copaxone is also known as copolymer-1 and cop-1. Multiple sclerosis is an autoimmune disease affects the brain and central nervous system due to the damage to the myelin sheath of the nerve cells, which results as demyelination of axons. Glatiramer acetate is a synthetic polypeptide analogue of myelin basic protein (MBP). Pharmacologically, Copaxone is a non-interferon and non-steroidal immunomodulator, which arrests the multiple sclerosis aggression. Glatiramer acetate is administrated by subcutaneous injections.

Chemically, glatiramer acetate is designated L-glutamic acid polymer with L-alanine, L-lysine and L-tyrosine, acetate salt. Its structural formula is:

          (Glu, Ala, Lys, Tyr)_x.xCH₃COOH 
          (C₅H₉NO₄.C₃H₇NO₂.C₆H₁₄N₂O₂.C₉H₁₁NO₃)_x.xC₂H₄O₂

Average molecular weight of glatiramer acetate is 5,000-11,000 daltons and the average molar fractions of the respective amino acids are: 0.141, 0.427, 0.095, and 0.338.

U.S. Pat. No. 3,849,550 describes the observation of MBP arrest in experimental allergic encephalomyelitis (a disease similar to multiple sclerosis) by immunotherapy agents. With continuous endeavours, glatiramer acetate is resulted as an advanced analogue for the treatment of multiple sclerosis with improved safety and efficacy.

U.S. Pat. Nos. 5,800,808; 5,981,589; 6,048,898 describes the process preparation of glatiramer acetate employing the N-carboxyanhydrides (NCAs) derived from alanine, γ-benzyl glutamate, N-trifluoroacetyl lysine, and tyrosine. Following the steps: polymerization, sequential cleavage of the γ-benzyl ester of glutamate and N∈-trifluoroacetyl derivative of lysine, acetate salt formation and final purification. U.S. Pat. No. 6,620,847 describes a process for the preparation of glatiramer acetate using the aqueous piperidine for trifluoroacetyl cleavage of lysine. U.S. Pat. No. 7,049,399 describes the process for preparation of polypeptide-1 using the catalytic transfer hydrogenation for the cleavage of γ-benzyl ester of glutamate. E.P. Pat. No. 1,807,467 describes the processes for preparation of glatiramer using NCAs of alanine, tyrosine, N-t-butoxycarbonyl L-Lysine, and protected glutamic acid, where in the protecting group is selected from γ-methoxybenzyl and γ-benzyl. U.S. Pat. No. 7,495,072 describes the process for the preparation of mixtures of polypeptides using purified hydrobromic acid. The major drawback of all these processes is the generation of impurities, multiple steps of purification and the variability in the secondary structures amongst different batches manufactured using the same process. HO Biocon Directions Pharmaceutical Company Address: Door No. A - 210, Gokul Arcade, Garevan Chowk, Sahar Road, Vile Parle East, Mumbai - 400057 Phone:022 6691 9761

EXAMPLES

Example 1

Preparation of Glatiramer Acetate Using Potassium Tert Butoxide

Preparation of Protected Polymer 2

Protected copolymer (1 gm) was taken in a mixture of THF and water, to that Lewatit K 2629 resin (1 gm) was added and stirred at 65° C. for 24 h. The resin was filtered through buckner funnel and washed with THF (5 ml).The reaction mass was distilled to 3-4 volume stage and water was added and the precipitated product was filtered and dried in VTD for 24 h at 40-45° C. Yield: 0.6 gm

Preparation of Glatiramer Acetate

To the stirred solution of protected polymer 2 (0.6 g) in anhydrous methanol (9 ml) was added potassium tertiary butoxide (0.6 g) and stirred for 1 hour. Reaction mass was concentrated under reduced pressure (below 35□ C.). To the reaction mass water (0.6 mL) was added and pH was adjusted with Glacial acetic acid to 5.5. Crude glatiramer acetate was isolated by crystallising with acetone. Crystallised solid was filtered and suck dried. Yield: 0.4 g

Crude glatiramer acetate obtained is subjected for gel permeation chromatography for purification.

Example 2

Preparation of Glatiramer Acetate Using Sodium Methoxide

Preparation of Protected Polymer 2

Protected copolymer (1 gm) was taken in a mixture of THF (8 ml) and water (ml), to that Lewatit K 2629 resin (1 gm) was added and stirred at 65° C. for 24 h. The resin was filtered through buckner funnel and washed with THF (5 ml).The reaction mass was distilled to 3-4 volume stage and water was added and the precipitated product was filtered and dried in VTD for 24 h at 40-45° C. Yield: 0.6 gm

Preparation of Glatiramer Acetate

To the stirred solution of protected polymer 2 (0.6 g) in anhydrous methanol (6 ml) was added a solution of sodium methoxide (0.9 g) in anhydrous methanol (4.5 mL)and stirred for 7 hours. Reaction mass was concentrated under reduced pressure (below 35° C.). To the reaction mass water (0.6 mL) was added and pH was adjusted with Glacial acetic acid to 6. Crude glatiramer acetate was isolated by crystallising with acetone. Crystallised solid was filtered and suck dried. Yield: 0.4 g

Crude glatiramer acetate obtained is subjected for gel permeation chromatography for purification.

Example 3

Preparation of Glatiramer Acetate Using TMSCl/NaI Followed by Sodium Methoxide

Protected polymer 1 (20 g) was charged in THF (200 ml) under nitrogen atmosphere, added sodium iodide (1 g) was added followed by trimethylsilyl chloride (20 ml) at room temperature and stirred for 3 h. The reaction mass was quenched after the completion of reaction with water (20 ml). The solids were filtered, washed with water (100 ml) and dried under high vacuum to obtain protected copolymer 2 (10 g).

The resulted protected polymer 2 was suspended in anhydrous methanol (100 ml), solution of sodium methoxide (15 g)in anhydrous methanol (75 ml) was added and stirred at room temperature for 7 h. pH was adjusted after the completion of the reaction to 6 with glacial acetic acid, and the mass was purified to obtain glatiramer acetate (6 g).

Example 4

Preparation of Glatiramer Acetate from Protected Polymer 3

Solution of sodium methoxide (1.5 g) in anhydrous methanol (7.5 ml) was added to protected copolymer 3 (1 g) in anhydrous methanol (10 ml) at room temperature and stirred for 7 h. pH was adjusted to 5 after completion of the reaction with glacial acetic acid. The resulted mass was purified to obtain glatiramer acetate (0.6 g).

The Far UV CD spectra, of Glatiramer acetate synthesised using the processes described in examples 1-4 exhibits the presence of random coils in the wavelength region 195-215 nm and alpha helices in the wavelength region of 222 nm. (FIG. 5) OWNER BANGALORE: Biotech major Biocon today said its Chairperson and Managing Director Kiran Mazumdar-Shaw

BANGALORE

BENGALURU, INDIA,




































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