| 89% |
Stage #1: With hydrogen iodide; hypophosphorous acid In water at 85 - 107℃;
Stage #2: With sodium hydroxide In water at 20 - 95℃; for 1 h; |
[00092] 4-lodopicolinic acid methyl ester (CYD-1-4). A mixture of 4-chloropicolinic acid methyl ester CYD-1-1 (4.8 g, 27.9 mmol), 57percent hydriodic acid (26.6 mL, 232.2 mmol) and 50percent) aqueous hypophosphorous acid (1.32 mL, 12.0 mmol) was stirred at 85°C for 2 h and then was stirred at 107°C overnight. The mixture was cooled to 95°C. At this temperature 8.4 mL of 10 N sodium hydroxide aqueous solution was added into the reaction mixture slowly. The mixture was cooled to room temperature and stirred for 1 h, and the yellow solid was precipitated. The precipitate was filtered, washed with cold water and dried under the vacuum overnight to give 4-iodopicolinic acid as a yellow solid (6.8 g, 89percent>). To a solution of 4-iodopicolinic acid (6.73 g, 27.0 mmol) in methanol (101 mL) was added concentrated sulfuric acid (508 μ), and the mixture was refluxed at 80°C for two days. The solvent was evaporated and the residue was taken up with the saturated sodium bicarbonate and extracted with ethyl acetate (three times). The organic layers were combined, washed with saturated brine, dried over anhydrous Na2S04 and evaporated. The residue was purified with silica gel column; eluting with 1 :3 ethyl acetate -hexane provided 4-iodopicolinic acid methyl ester (CYD-1-4) as a yellow solid (2.88 g, 40percent for two steps); mp 73-74°C; 1H NMR (600 MHz, CDCls) δ 8.50 (d, 1H, J = 1.2 Hz), 8.39 (d, 1H, J= 5.4 Hz), 7.87 (dd, 1H, J = 1.8 Hz and 4.8 Hz), 4.02 (s, 3H). |
| 66% |
Stage #1: With hydrogen iodide; hypophosphorous acid In water at 85 - 107℃;
Stage #2: at 20 - 95℃; for 1.5 h; |
A mixture of picolinic acid (Aldrich) (20 g, 162 mmol, [1] equiv) and sodium bromide (33.43 g, 325 mmol, 2 equiv) in thionyl chloride (81 mL) was refluxed for 5 h. The solvent was removed under vacuum. Absolute methanol (160 mL) was added and the mixture was stirred at rt for 30 minutes. The solvent was evaporated, and the residue was taken up in 5percent sodium bicarbonate and extracted with ethyl acetate (3x). The organic layers were combined and dried over [MGS04] and evaporated. The residue was purified by chromatography to give 4- chloropicolinic acid methyl ester as a white solid (19.9 g, 72percent) [: 1H] NMR (300 MHz, [CDC13)] 8 8.63 (d, J= 5.4, 1), 8.13 (d, J= 2.1, 1), 7.48 (dd, J= 2.0, 5.3, 1), 4.00 (s, 3). [[0217]] A mixture of 4-chloropicolinic acid methyl ester (2.4 g, 14.1 mmol), 57percent hydroiodic acid (13.3 mL) and 50percent aqueous hypophosphorous acid (0.66 mL) was stirred at 85 [°C] for 2 h and then was stirred at [107 °C] overnight. The mixture was cooled to 95 [°C.] At this temperature over 30 minutes 10 M sodium hydroxide aqueous solution (4.2 mL) was added, followed by the addition of water (15.2 mL). The mixture was cooled to rt and stirred at rt for [LH.] The precipitate was filtered, washed with cold water and dried under high vacuum overnight to give 4-iodopipecolinic acid 13a (3.5 g, [66percent) : 1H] NMR (300 MHz, DMSO d6) 8 8. [39] (d, [J=] 5.1, 1), [8. 35] (d, [J= 1.] 8,1), 8.07 (dd, [J= 1.] 7,5. 2, [1) ;] MS (ESPOS): 250.2 [M + H] [+.] [[0218]] To a mixture of 7-Me MTL HCl salt 2b [(RAPOS;=ME,] R2=Me) (200 mg, 0.69 mmol, [1] equiv) in dry DMF (1.8 mL) at [0 °C] was added triethylamine (0.50 mL, 3.61 mmol, 5.2 equiv), followed by the addition of BSTFA (0.28 mL, 1.04 mmol, 1.5 equiv). The reaction mixture was stirred at [0 °C] for 10 minutes, and then was stirred at rt for 50 minutes. To the reaction mixture was added the acid 13a (341 mg, 0.90 mmol, 1.3 equiv) and HATU (423 mg, 1.11 mmol, 1.6 equiv). The reaction mixture was stirred at rt for 3 h. The reaction mixture was evaporated to dryness, taken up in ethyl acetate, washed with water [(1] x), sat. [NAHC03] [(1] x) and brine. The organic layer was dried over [NA2S04] and evaporated to give a yellow residue which was dissolved in methanol (20 mL) to which was added dry Dowex resin (250 mg). The reaction mixture was stirred at rt for 1 h. The resin was removed by filtration and the crude product eluted with 2M ammonia in methanol. The methanolic eluent was evaporated, and the resulting residue was purified by chromatography to provide a white solid 13b (Rl=Me, R2= Me, [R3=H)] (250 mg, 75percent) [: LH NMR] (300 MHz, CD30D) 8 8.46 (d, [J= 1.] 8,1), 8.30 (d, J= 5.4, 1), 7.98 (dd, J= 1.8, 5.1, 1), 5.25 (d, J= 6.0, 1), 4.32-4. 23 (m, 2), 4.09 (dd, J= 5.7, 10.2, 1), 3.87 (d, J= 3.0, 1), 3.54 (dd, J= 3.3, 10.2, 1), 2.24-2. 15 (m, 1), 2.11 (s, 3), 0.99-0. 96 (m, 6); MS (ESPOS): [483.] 5 [M + [H] +] ; MS (ESNEG): 481.4 [[M-H]-.] [0219] To a dry flask was added 13b [(RL=ME,] R2= Me, R3=H) (133.9 mg, [0.] 28 mmol, 1 equiv), triphenylphosphine (46.7 mg, 0.18 mmol, 0.64 equiv), copper (I) iodide [(33.] 9 mg, 0.18 mmol, 0.64 equiv), palladium acetate (20 mg, 0.09 mmol, 0.32 equiv) and triethylamine (1.6 mL). The mixture was deaerated with nitrogen, followed by addition of 3-prop-2-ynyl- cyclopentane (120 mg, [1.] 11 mmol, 4 equiv). The mixture was stirred at 50 oC overnight. The solvent was removed under vacuum to give a dark residue. The residue was purified by chromatography to give 13c (Rl=Me, R9'= 3-cyclopentyl-prop-1-ynyl, R2= Me, R3=H) as a yellow solid (106 mg, 83percent): 1H NMR (300 [MHZ, CD30D) 6] 8.55 (d, J= 4.8, 1), 7.98 (s, 1), 7.47 [(DD,] [J=] 1.7, 5.0, 1), 5.26 (d, [J=] 5.4, [1),] 4. [33-4.] 22 (m, 2), 4.10 (dd, [J=] 5.5, 10.4, 1), 3.86 (d, J= 3.3, 1), 3.55 (dd, J= 3.3, 10.5, 1), 2.49 (d, J= 6.9, 2), 2.26-2. 12 (m, 2), 2.11 (s, 3), 1.93- 1.82 (m, 2), 1.73-1. 55 (m, 4), 1.43-1. 31 (m, 2), 1.00-0. 96 (m, 6); MS (ESPOS): 463.6 [M [+ H] +] ; MS (ESNEG): 461.5 [M-H]-. |
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