反应详情

To a stirred suspension of 2(R,S)-methylthiazolidine-4(R)-carboxylic acid (8.51 g, 57.9 mmol) prepared according to Nagasawa et al., J. Med. Chem., 27, 591 (1984), which is incorporated herein by reference, in dry CH3CN (100 mL) under a N2 atmosphere was added bis-(trimethylsilyl)trifluoroacetamide (17.0 mL, 17.7 g, 68.7 mmol, obtained from Sigma Chemical Co., "BSTFA") and the mixture was heated under reflux for 1.25 hours. The solids dissolved within 10 minutes of heating. After cooling to room temperature, N-phthaloyl-L-glutamic anhydride (15.0 g, 58.0 mmol) prepared according to Elbefling et al., Org. Prep. Proceed. Int., 11, 67 (1979), which is incorporated herein by reference, was added, followed by dry CH3CN (25 mL). After 5 days at room temperature the solvent was evaporated in vacuo. To the resultant pale yellow thick oil (41.1 g) were added with stirring under a N2 atmosphere, 1.0M Et3N in CH3OH (220 mL) and 2.0M NH2NH2.H2O in 50% aqueous CH3OH (73 mL). After 2 days of stirring the solvent was evaporated in vacuo. The resultant thick, white, semisolid (51.8 g) was suspended in H2O (150 mL) and the solvent evaporated again to give 49.7 g of a thick, white oil. This was poured into warm H2O (350 mL) with swirling. The resultant precipitate of phthalhydrazide was removed by filtration and the filter cake was rinsed with H2O (approximately 100 mL). The combined filtrate was acidified to pH 3.5 with 1.0N HCl, whereupon more phthalhydrazide precipitated. This was removed by filtration, and the filtrate was evaporated in vacuo, keeping the temperature under 40° C., to give 35.8 g of a thick, pale yellow oil whose NMR spectrum showed the presence of much Et3N and some phthalhydrazide in addition to the desired product. The oil was, therefore, resuspended in H2O (75 mL), the mixture was stirred, and the additional solids that precipitated were removed by filtration. The filtrate was evaporated to incipient dryness in vacuo to give a thick oil (24.6 g).

1. customprepared
2. temperaturethe mixture was heated
3. temperatureunder reflux for 1.25 hours
4. dissolutionThe solids dissolved within 10 minutes
5. temperatureof heating
6. additionwas added
7. customAfter 5 days at room temperature the solvent was evaporated in vacuo
8. additionTo the resultant pale yellow thick oil (41.1 g) were added
9. stirringAfter 2 days of stirring the solvent
10. customwas evaporated in vacuo
11. customthe solvent evaporated again
12. customto give 49.7 g of a thick, white oil
13. additionThis was poured
14. customThe resultant precipitate of phthalhydrazide was removed by filtration
15. washthe filter cake was rinsed with H2O (approximately 100 mL)
16. customprecipitated
17. customThis was removed by filtration
18. customthe filtrate was evaporated in vacuo
19. customunder 40° C.
20. customto give 35.8 g of a thick, pale yellow oil whose NMR spectrum