反应详情

温度

45 °C

Nitrogen was bubbled through a suspension of 2-amino-5-chlorothiazole hydrochloride (25.0 g, 146 mmol) in dichloromethane (1000 ml) for 10 minutes before the addition of piperidine (13.0 g, 15.0 ml, 150 mmol) via syringe. 2,4-Dimethoxybenzaldehyde (22.1 g, 133 mmol) was added followed by freshly dried 3 Å molecular sieves (ca. 40 g). The mixture was stirred at 45° C. under nitrogen fro 16 hours. Upon cooling to room temperature the mixture was filtered through a pad of Celite™, washing with dichloromethane (2000 ml) before concentrating in vacuo to give a yellow solid, 58.2 g. This residue was dissolved in methanol (1250 ml) and sodium borohydride (13.0 g, 340 mmol) was added portionwise. Upon complete addition the mixture was heated to 50° C. for 30 minutes before cooling to room temperature and stirring under nitrogen for 16 hours. The solvent was concentrated in vacuo and the residue partitioned between ethyl acetate (300 ml) and water (500 ml). The layers were separated and the aqueous was extracted with ethyl acetate (3×300 ml). The combined organics were washed with water (300 ml), saturated aqueous sodium chloride solution (300 ml), dried over magnesium sulphate, filtered and concentrated in vacuo to give a red-brown solid, 41.6 g. This residue was dissolved in ethyl acetate and passed through a plug of silica. Concentration in vacuo afforded a red-brown solid, 39.3 g, which was subsequently triturated with diethyl ether (ca. 500 ml) and stirred for 60 hours. The solid was filtered and air-dried to give the title compound as a white solid, 12.1 g, 32% yield. The mother liquor was concentrated in vacuo to give a brown solid, 25 g, which was stirred in diethyl ether:heptane (2:3, 500 ml). The solid material was filtered and air-dried to give the title compound as an off-white solid, 13.2 g, 35% yield.

1. temperatureUpon cooling to room temperature the mixture
2. filtrationwas filtered through a pad of Celite™
3. washwashing with dichloromethane (2000 ml)
4. concentrationbefore concentrating in vacuo
5. customto give a yellow solid, 58.2 g
6. additionUpon complete addition the mixture
7. temperaturewas heated to 50° C. for 30 minutes
8. temperaturebefore cooling to room temperature
9. stirringstirring under nitrogen for 16 hours
10. concentrationThe solvent was concentrated in vacuo
11. customthe residue partitioned between ethyl acetate (300 ml) and water (500 ml)
12. customThe layers were separated
13. extractionthe aqueous was extracted with ethyl acetate (3×300 ml)
14. washThe combined organics were washed with water (300 ml), saturated aqueous sodium chloride solution (300 ml)
15. dry with materialdried over magnesium sulphate
16. filtrationfiltered
17. concentrationconcentrated in vacuo
18. customto give a red-brown solid, 41.6 g
19. concentrationConcentration in vacuo
20. customafforded a red-brown solid, 39.3 g, which
21. customwas subsequently triturated with diethyl ether (ca. 500 ml)
22. stirringstirred for 60 hours
23. filtrationThe solid was filtered
24. customair-dried