| 73% |
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; |
EXAMPLES EXAMPLE 1: Preparation of 2, 2-Dimethyl-N-pyridinyl-propionamides 1A : 2, 2-Dimethyl-N-pyridin-4-yl-propionamide [081] Following procedures generally taught in J. A. Turner, J. Org. Chem. 1983, 48, 3401- 3408, a solution of pivaloyl chloride (13.5 mL, 110 mmol) in CH2C12 (20 mL) was slowly added to an ice-cold solution of 4-aminopyridine (9.41 g, 100 mmol) and triethylamine (17.4 mL, 125 mmol) in CH2C12 (150 mL). After addition was complete, the resulting mixture was warmed to room temperature and stirred for 2 h. The solution was poured into water, the CH2C12 layer was washed with dilute NaHC03, dried over Na2SO4, and evaporated to leave a light brown solid. Recrystallization from EtOAc/hexanes afforded the product as a white crystal, which was collected by vacuum filtration (13.03 g, 73%). 1H NMR (400 MHz, CDC13) 8 8. 50 (d, J= 4.8 Hz, 2 H), 7.50 (d, J= 4.8 Hz, 2 H), 7.44 (br s, 1 H), 1. 33 (s, 9 H). MS (LR-APCI) calcd. for CloH1sN20 (M+H) 179.1 ; found 179.1. |
| 73.9% |
With triethylamine; In chloroform; at 0 - 20℃; for 1.16667h; |
To a stirred solution of 4-amino pyridine (A; 5 g, 53.12 mmol) in CHCI3 (200 mL) were added triethylamine (TEA or Et3N) (11.5 mL, 106.2 mmol) followed by pivaloyl chloride (7.15 mL, 69 mmol) dropwise at 0C over a period of 10 minutes (min). The reaction mixture was warmed to RT and stirred for 1.5 hours (h). The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was washed with saturated sodium bicarbonate (NaHC03) solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. The obtained crude material was purified by silica gel column chromatography eluting with 10% methanol (MeOH)/dichloromethane (CH2CI2) to afford B (7 g, 73.9%) as an off-white solid. *H NMR (200 MHz, DMSO-de): delta 9.54 (bs, NH), 8.40 (d, J = 5.8 Hz, 2H), 7.67 (d, / = 6.4 Hz, 2H), 1.23 (s, 9H). MS (ESI): m/z 179 [M++l]. |
| 70% |
With triethylamine; In dichloromethane; at 0 - 20℃; for 3h; |
To a solution of 1 .88 g (20.0 mmol, 1 eq.) of 4-aminopyridine and 3.6 mL (26.0 mmol, 1 .3 eq.) of triethylamine in 30 mL of DCM, cooled to 0C, were added 2.7 mL (22.0 mmol, 1 .1 eq.) of trimethylacetyl chloride in 4 mL of DCM. After 2 hours, the mixture was stirred one hour at room temperature. Then, 40 mL of water were added. The aqueous layer was extracted with 20 mL of dichloromethane. The organic phase was washed with 20 mL of aqueous NaHC03, dried, filtered and concentrated. Recrystallisation in PE/EtOAc 8:1 provided 2.50 g (14.0 mmol, 70%) of VII as a white solid. Rf=0.07 (PE/EtOAc 2:1 ). 1H NMR (300 MHz): delta = 8.46 (d, J = 5.5 Hz, 2 H), 7.73 (broad, 1 H), 7.49 (dd, J = 4.9 Hz, J = 1 .4 Hz, 2 H), 1 .30 (s, 9 H) ppm. 13C NMR (75 MHz): delta = 177.5, 150.7, 145.3, 1 13.9, 40.1 , 27.5 ppm |
| 70% |
With triethylamine; In dichloromethane; at 0 - 20℃; for 3h; |
To a solution of 1.88 g (20.0 mmol, 1 eq.) of 4-aminopyridine and 3.6 mL (26.0 mmol, 1 .3 eq.) of triethylamine in 30 mL of DCM, cooled to 0C, were added 2.7 mL (22.0 mmol, 1 .1 eq.) of trimethylacetyl chloride in 4 mL of DCM. After 2 hours, the mixture was stirred one hour at room temperature. Then, 40 mL of water were added. The aqueous layer was extracted with 20 mL of dichloromethane. The organic phase was washed with 20 mL of aqueous NaHC03, dried, filtered and concentrated. Recrystallisation in PE/EtOAc 8:1 provided 2.50 g (14.0 mmol, 70%) of VII as a white solid. Rf=0.07 (PE/EtOAc 2:1 ). 1H NMR (300 MHz): delta = 8.46 (d, J = 5.5 Hz, 2 H), 7.73 (broad, 1 H), 7.49 (dd, J = 4.9 Hz, J = 1.4 Hz, 2 H), 1.30 (s, 9 H) ppm. 13C NMR (75 MHz): delta = 177.5, 150.7, 145.3, 113.9, 40.1 , 27.5 ppm |
| 68% |
With triethylamine; In dichloromethane; at 0 - 20℃; for 18h; |
A solution of trimethyl acetyl chloride (32.5 mL, 0.264 mol) in dry dichloromethane (50 mL) was added drop wise over 1 h to a stirred suspension of 4-aminopyridine (22.60 g, EPO <DP n="50"/>""0.240 ffiotra?tf &iethyf?BM?fef41.8 mL, 0.300 mol) in dry dichloromethane (360 mL) at 0 0C under nitrogen. The ice bath was removed and the reaction allowed to warm to r.t. overnight. After 17 h, the pale brown mixture was poured into water (500 mL). The organic layer was separated and washed with a dilute aqueous solution of sodium hydrogen carbonate (400 mL). The organic layer was separated, dried over sodium sulfate, filtered and the solvent evaporated in vacuo. The crude solid was recrystallized from ethyl acetate (75 mL) / hexane (50 mL), washed with diethyl ether (2 x 10 mL) and air dried to yield N-(pyridin-4-yl)pivalamide (29.11 g, 68%) as colourless plate like crystals. 1H NMR : delta (CDCl3, 400 MHz) 1.33 (s, 9 H), 7.50 (d, J = 6 Hz, 2 H), 7.56 (br. s., I H), 8.49 (d, J = 6 Hz, 2 H). |
| 66% |
With triethylamine; In dichloromethane; at 0 - 20℃; for 2.25h; |
Step 1: A solution of trimethylacetylcholride (423 mg, 3.51 mmol, 1.1 eq) in dichloromethane was slowly added to an ice cooled solution of pyridin-4-amine (300 mg, 3.19 mmol) and triethylamine (0.56 mL, 3.98 mmol, 1.25 eq) of dichloromethane. The resulting mixture was stirred in and ice bath for 15 min and then at room temperature for 2 h and poured into water. The reaction mixture was washed with dilute NaHC03 dried over Na2S04, and evaporated. The crude was purified by column chromatography to give N-(pyridin-4-yl)piva.amide (377 mg, 66 %). |
| 66% |
With triethylamine; In dichloromethane; at 20℃; for 2.25h;Cooling with ice; |
Step 1: A solution of trimethylacetylcholride (423 mg, 3.51 mmol, 1.1 eq) in dichloromethane was slowly added to an ice cooled solution of pyridin-4-amine (300 mg, 3.19 mmol) and triethylamine (0.56 mL, 3.98 mmol, 1.25 eq) of dichloromethane. The resulting mixture was stirred in and ice bath for 15 min and then at room temperature for 2 h and poured into water. The reaction mixture was washed with dilute NaHCO3 dried over Na2SO4, and evaporated. The crude was purified by column chromatography to give N-(pyridin-4-yl)pivalamide (377 mg, 66%). |
| 40% |
|
A solution of pivaloyl chloride (13.4 g, 1 1 1 mmol) in DCM (20 mL) was slowly added to a cooled (0 C) solution of pyridin-4-amine (10 g, 106 mmol) and triethylamine (26.7 g, 265 mmol) in DCM (80 mL). After addition, the icebath was removed and the resulting mixture was stirred at 20 C for 6 hours. The mixture was poured into water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic extract was washed with saturated NaHC03 solution (100 mL) and brine (100 mL), dried over MgS04, and concentrated under reduced pressure. The residue was re-crystallized from EtO Ac/petroleum ether to give the desired product as white crystals (7.9 g, 40% yield). LCMS (ESI) m/z: 179.1 [M+H+] . |
|
With triethylamine; In dichloromethane; |
Step 1. Preparation of 2,2-Dimethyl-N-pyridin-4-yl-propionamide A solution of pivaloyl chloride (1.1 eq.) in CH2Cl2 is added to a solution of 4-aminopyridine (1 eq.) and triethylamine (1.2 eq.) in CH2Cl2, stirred at 02C for 2 h, washed with aqueous sodium bicarbonate, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography over silica gel to afford the title propionamide compound. |
|
With triethylamine; In dichloromethane; |
Example I To a mixture of 20g of 4-Aminopyridine and 37 mL of triethylamine in 380 mL of methylene chloride is added 28.8 mL of pivaloyl chloride in a dropwise fashion. After 1 hour at room temperature the reaction mixture is washed with water and sodium bicarbonate solution, dried over magnesium sulfate and the solvent is removed in vacuo. The residue is triturated with hexane to afford 4-trimethylacetamidopyridine as a white solid. |
|
With triethylamine; In dichloromethane; at -78 - 20℃; |
To a 1.1 M solution of 4-aminopyridine in CH2C12 at-78C was added 1.3 equiv of Et^N followed by 1.1 equiv of a 5.9 M solution of trimethylacetyl chloridein CH2C12- After allowing the reaction to warm to room temperature overnight, this mixture waspoured into a separatory funnel containing brine/CH2Cl2. The layers were separated and the aqueouslayer was extracted several times with CH2C12- The combined organic layer was dried over anhydrousNa2SO4, filtered and concentrated. The crude material was further purified by a pad of silica gel byeluting with a gradient from 60% EtOAc/hexanes to 100% EtOAc and the product was swished inhexanes twice to yield the title compound as an off-white solid. IH NMR (acetone-dg) 5 8.95 (1H, br s),8.42 (2H, dd), 7.69 (2H, dd), 1.31 (9H, s). |
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