Method for synthesizing imidazole-amino acid derivative and related compound
A technology of azole compounds and alkylating agents, applied in the field of 2-substituted azole derivatives and new intermediate compounds
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Embodiment 1
[0301]
[0302]A solution of commercially available N-tritylserine methyl ester (15.0 g, 41.5 mmol) in 350 mL of toluene was stirred with triethylamine (16 mL, 115 mmol) until the solids dissolved. A solution of phosgene (20% (w / w) in toluene, 25 ml, 47.2 mmol) was then added and the solution was stirred for 2 hours. The mixture was then poured into 100 ml 1N HCl and the layers were separated. After adding 40ml of 3N NaOH to the aqueous layer, it was extracted twice with 100ml of 1:1 toluene:dichloromethane. The combined organic layers were then washed once with 100 ml 1N HCl, twice with 100 ml 1N NaOH and once with 100 ml brine. The resulting solution was dried over sodium sulfate and passed through a pad of silica gel (0.5", 500ml sintered glass funnel). The silica gel was washed with 250ml ethyl acetate and concentrated in vacuo to give a crude foam (16.5g, >100%).
[0303] The solid prepared above was dissolved in 300 ml dry THF and cooled to an internal temperature o...
Embodiment 2
[0306]
[0307] Compound 1 (450 mg, 1.25 mmol) and 1-benzylimidazole (159 mg, 1.0 mmol) were dissolved in 5 ml of acetonitrile. Then N,N-dimethylcarbamoyl chloride (0.125ml, 1.35mmol) and N,N-diisopropylethylamine (0.53ml, 3.0mmol) were added. After stirring for 3 days, the solution was poured into 10 ml of water and 20 ml of dichloromethane. The layers were separated and the aqueous layer was extracted with an additional 10 mL of dichloromethane. The combined organic extracts were washed successively with 20 ml of 1N sodium hydroxide and 20 ml of brine, dried over sodium sulfate, and purified by silica gel column chromatography (10% ethyl acetate and hexane mixture to 75% ethyl acetate). Compound 2 was isolated (420 mg, 72% yield, off-white foam).
[0308] HRMS: 587.2662 (MH + The calculated value is 587.2658).
Embodiment 3
[0310]
[0311] Compound 2 (600 mg, 1.02 mmol) was dissolved in 1% water in trifluoroacetic acid and stirred at ambient temperature until cleavage of the trityl group was complete. After the solution was concentrated in vacuo, the crude intermediate was dissolved in 18 ml of 2:1 ethanol:water. Solid potassium hydroxide (2.0 g, 30 mmol) was added and the solution was heated to reflux for 18 hours. The intermediate was extracted by acidifying the solution with concentrated hydrochloric acid, partitioned between 30ml ether and 20ml water. The layers were separated, and after the organic layer was extracted with 20 ml of 1N hydrochloric acid, the combined aqueous extracts were neutralized with solid sodium bicarbonate. 1,4-2 After alkane (25ml) was added to the aqueous solution, potassium hydroxide (560mg, 8.5mmol) and di-tert-butyl dicarbonate (0.3ml, 1.3mmol) were added. The solution was stirred at ambient temperature for 1 hour, then heated to reflux for 20 minutes, cool...
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