| 92% |
With hydrogen;palladium 10% on activated carbon; In methanol; under 760.051 Torr; |
4-Butylpyridine was prepared by adding potassium-t-butoxide (0.68 g, 6 mmol) to propylphosphonium bromide (Aldrich) (2.4 g, 6.0 mmol) in THF (10 mL), at [0 C] and stirring at room temperature for 1 hour. Pyridine-4-carbaldehyde (428 mg, 4 mmol) was added and the reaction mixture stirred for 2h. The reaction mixture was then poured into water and extracted with ethyl acetate. The product obtained after removing the solvent was taken as such in methanol [(30] mL) to which palladium on carbon (10%, [300] mg) was added and hydrogenated at 1 atm pressure over night. Removal of solvent and purification on column chromatography using ethyl acetate resulted in pure product 4-butylpyridine (500 mg, 92%): [[0318] 1H] NMR (CDC13): [8] 8.42 (d, [J=] 6.0, 2), 7.05 (d, [J=] 6.0, 1), 2.60 (t, [J=] 6.5, 2), 1.62 (m, 2), 1. [37] (m, 2), 0.93 (t, [J=] 7.0, 3). MS (ES+): [136 (M+1).] [[0319]] 4-Butylpyridine-2-carboxylic acid, compound [(10B)] (R9 = butyl), was made employing general Method P. To [4-BUTYLPYRIDINE] (2 g, 0. [014] mol) in acetic acid (15 mL), hydrogen peroxide (30%, 5 mL, 0.056 mol) was added and refluxed over night. After removing the solvent, the residue was dissolved in DCM dried over magnesium sulfate and taken as such for the next step. To the compound from the previous step in dichloromethane (10 mL) trimethylsilyl cyanide (3.92 mL, 0.029 mol) and dimethylcarbamoyl chloride (2.67 mL, 0. [028] mol) was added and stirred at room temperature for 24 hours. Aqueous potassium carbonate (10%, 50 mL) was added and extracted with dichloromethane (100 mL). The crude product obtained on removal of solvent was taken up in hydrochloric acid (6N, 30 mL) and refluxed for 24 hours. Removal of acid followed by crystallization of the crude product from acetonitrile resulted in acid [10B] [(R9 =] butyl) [(1.] 5g, 60%). [[0320]'H] NMR [(CDC13)] : 8 8.92 (d, [J=] 6.0, 1), 8.65 (s, 1), 8.27 (m, 1), 3.23 (t, [J=] 6.5, 2), 1.98 (m, 2), 1.67 (m, 2), 1.20 (t, [J=] 7.0, 3). MS (ES-): 178 (M-1). [[0321]] To the amine, compound 2b (Rl=Me, [R=ME),] (140 mg, 0.56 mmol) in DMF (3 mL), BSTFA (0.59 mL, 2.24 mmol) and triethylamine (0.18 mL, 1.26 mmol) were added at [0 C] and then stirred at room temperature for 3 hours. Acid [10B (R9] = butyl) (203 mg, 1.13 mmol) and HATU (319 mg, 0.84 mmol) were added and the reaction mixture was stirred for 4 more hours at room temperature. The DMF was removed and the residue was extracted with ethyl acetate (100 mL) and washed with saturated bicarbonate (40 mL). The product obtained on removal of solvent was taken up in methanol and treated with Dowex [HF] resin for 1 hour. After filtering the resin, methanol was removed to obtain the crude product. The product was then purified on silica gel column using ethyl acetate as eluent to provide for compound [L LB (RL=ME, R2=ME] [R3--H,] R9 = butyl) (200 mg, 86 %). [[0322] 1H] NMR (CDC13) [8] 8.40 (d, J= 4.2, 1), 8.01 (s, 1), 7.29 (m, 1), 5.40 (d, J = 5. 4, [1),] 4.02-4. 36 (m, 3), 4.80 (s, 1), 3.48-3. 60 (m, 1), 3.72 (t, J= 6.0, 2), 2.49 (m, [1),] 2.20 9s, 3), 1. 67 (m, 4), 1.40 [(M,] 3), 0.98-1. 18 (m, 9). Mass 413 [(M+1).] [[0323]] To compound 1 lb (Rl=Me, R2=Me [R3=H,] R9 = butyl) (200 mg, 0.49 mmol} in methanol (5 mL), water (10 mL) and acetic acid (5 mL), platinum dioxide (100 mg, 0.44 mmol) was added and hydrogenated at 60 psi for 16 h. After filtering the catalyst, the solvent was stripped off to obtain the crude product, which was then purified on silica gel column chromatography using 20% methanol in dichloromethane as eluent. The lower Rf fractions provided the title compound (60 mg, 29%). [[0324] 1H] NMR [(CDC13)] : 8 5.20 (d, J= 3.6, 1), 4.20 (dd, J= 3.0, 4.8, 1), 4.04 (m, 2), 3.80 (d, J =3. 0,1), 3.61-3. 66 (m, 1), 3.52 (dd, J= 3.3, 10.2), 2.88 (m, 1), 2.17 (m, 1), 2.14 (s, 3), 1.87 (m, 2), 1.62 (m, 2), 1.32 (m, 6), 0.89 (m, 9); MS (ES+): 419 (M+1). |
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