| 81% |
Stage #1: 2-chloro-3-aminopyridine With sodium hexamethyldisilazane In tetrahydrofuran at -10℃; for 0.166667h;
Stage #2: di-<i>tert</i>-butyl dicarbonate In tetrahydrofuran for 0.5h; Further stages.; |
|
| 81% |
Stage #1: 2-chloro-3-aminopyridine With sodium hexamethyldisilazane In tetrahydrofuran at -10℃; for 0.5h; Inert atmosphere; Cooling with acetone-dry ice;
Stage #2: di-<i>tert</i>-butyl dicarbonate In tetrahydrofuran at -10℃; for 1h; |
|
| 80% |
In 1,4-dioxane at 80℃; Inert atmosphere; |
1.1 Step 1) Preparation of compound (II)
Under a nitrogen atmosphere,50.0g of 2-chloro-3-amino-pyridine (I) (0.39mol, 1.0eq) was added to the reaction bottle in sequence,135.8 g of di-tert-butyl dicarbonate (0.63 mol, 1.6 eq) and 150 g of 1,4-dioxane,Stir to dissolve. Raise the temperature to 80 and stir the reaction,Central control detection, complete raw material reaction.Saturated saline was added for washing twice, and the organic layer was distilled under reduced pressure to a non-fraction.Filtration gave 71.1 g of light yellow solid (80% yield), which was Compound II. |
| 74.2% |
With dmap In dichloromethane at 20℃; for 3h; |
36 Preparation of N-(3-(4-amino-2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide
To a solution of 2-chloropyridin-3 -amine (12.9 g, 0.1 mol, 1 eq.) and DMAP (13.4 g, 0.11 mmol, 1.1 eq.) in DCM (150 mL) was added Boc20 (24.0 g, 0.11 mmol, 1.1 eq.) dropwise at r.t. The resulting mixture was stirred at r.t. for 3 h, then concentrated. The resulting residue was purified via flash column chromatography (EA/PE=l/30, v/v) to afford tert-butyl (2-chloropyridin-3-yl)carbamate (16.99 g, 74.2% yield). |
| 67% |
With triethylamine |
|
| 47% |
With dmap; triethylamine In dichloromethane at 20℃; for 16h; |
Step 1: tert-butyl (2-chloropyridin-3-yl)carbamate
To a stirred solution of 2-chloropyridin-3-amine (10.00 g, 78.00 mmol) in DCM (50 mL) were added Et3N (23.7 mL, 234.0 mmol), Boc anhydride (25.5 g, 117.0 mmol) and DMAP (0.95 g, 7.8 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured in to water (100 mL) and the aqueous layer was extracted with dichloromethane (100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by chromatography on SiO2 (eluting with 11% ethyl acetate in hexane) to afford the title compound (8.5 g, 47%). MS (ESI-MS): m/z calcd for C10H13ClN2O2[MH] + 228.07, found 229.1 & 231.1 [M+1 & M+3] . |
| 21% |
With triethylamine In dichloromethane at 0 - 25℃; for 18h; |
100.1 N-(2-Chloro-3-pyridyl) tert-butyl carbamate
2-Chloropyridin-3-amine (30.0 g, 233 mmol) was dissolved in dichloromethane (250 mL) and triethylamine (47.2 g, 467 mmol) was added. Di-tert-butyl dicarbonate (102 g, 467 mmol) was added dropwise at 0°C. The reaction was stirred at 25°C for 18 hours. Water (100 mL) was added to quench the reaction. The reaction was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15:1 petroleum ether / ethyl acetate, Rf = 0.6) to give N-(2-chloro-3-pyridyl) tert-butyl carbamate (11.0 g, as a white solid) with a yield of 21%. 1H NMR: (400 MHz, DMSO-d6) δ 8.89(s, 1H), 8.17-8.16(m, 1H), 8.03-8.01(m, 1H), 7.43-7.39(m, 1H), 1.47(s, 9H). |
| 21% |
With triethylamine In dichloromethane at 0 - 25℃; for 18h; |
57.1 Tert-butyl N-(2-chloro-3-pyridinyl) carbamate
2-Chloropyridin-3-amine (30.0 g, 233 mmol) was dissolved in methylene chloride (250 mL), and then triethylamine (47.2 g, 467 mmol) was added. Di-tert-butyl dicarbonate (102 g, 467 mmol) was added dropwise at 0° C. The reaction solution was stirred at 25° C. for 18 hours. The reaction was quenched by adding water (100 mL). The reaction solution was extracted with ethyl acetate (100 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (15:1 petroleum ether/ethyl acetate, Rf-0.6) to give tert-butyl N-(2-chloro-3-pyridinyl) carbamate (11.0 g, white solid) with a yield of 21%. 1H NMR: (400 MHz, DMSO-d6) δ8.89 (s, 1H), 8.17-8.16 (m, 1H), 8.03-8.01 (m, 1H), 7.43-7.39 (m, 1H), 1.47 (s, 9H). |
|
With dmap; triethylamine In dichloromethane |
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|
With potassium hexamethylsilazane In tetrahydrofuran at 20℃; for 2h; |
To a solution of 2-chloropyridin-3-amine (7-1) (2.0Og, 15.6 tnmol) in THF (50 mL) was added a 0.5M solution of KHMDS in THF (68.5 mL) and then di-tert-butyl dicarbonate (3.73 g, 17.1 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-60% EtOAc/Hexane) to give tert-butyl (2-chloropyridin-3-yl)carbamate (7-2) as a colorless solid. |
|
With sodium hexamethyldisilazane In tetrahydrofuran |
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Stage #1: 2-chloro-3-aminopyridine With sodium hexamethyldisilazane In tetrahydrofuran at -15℃; for 0.5h; Inert atmosphere;
Stage #2: di-<i>tert</i>-butyl dicarbonate In tetrahydrofuran at -15 - 20℃; Inert atmosphere; |
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