4.4- diethyl-oxazolidine-2,5-dione

Amino-2-phenyl-propionic acid and 2-amino-2-ethylbutyric acid, 1172, react with benzyl chloroformate in aqueous alkali and then with thionyl chloride to give 4-methyl-4-phenyl-oxazolidin-2,5-dione [854] and 4,4-diethyl-oxazolidine-2,5-dione 1174 [855],... 

The convergent synthesis of these compounds is rather simple. On the one side, the required a-keto ester may be synthesised from diethyl oxalate by a Grignard reaction. On the other side, alanine or trifluoroacetyllysine is coupled with proline via the oxazolidine-2,5-dione (the so-called Leuchs anhydride ). The two halves are combined by reductive amination. The diastereoselectivity of the hydrogenation is dependent on the choice of catalyst. With Raney nickel, the diastereoselectivity lies in case of enalapril at 87 13 and for Iisinoprii at 95 5 in favour of the desired diastereomers. In the case of Iisinoprii, there follows a final hydrolysis of the ester and amide function. The active material is ultimately purified by crystallisation. 

Similarly, 4-(4-benzyloxybenzyl)-4-methyl-oxazolidine-2,5-dione 1185 was formed by reacting the corresponding protected amino acid 1184 with PBrs in diethyl ether [860],... 

Acetylsulfanyl-4-methyl-oxazolidine-2,5-dione 1189 was prepared with PCI5 in diethyl ether [863]. 

Similarly, (i )-4-benzylsulfanylmethyl-oxazolidine-2,5-dione was prepared from S-benzyl-N-Cbz-L-cysteine and PCI5 in diethyl ether [867], while (S)-3-(oxazolidine-2,5-dion-4-yl)propionic acid esters were prepared from N-Bbzo-L-glutamic acid 5-alkyl esters and PCI5 [868]. 

Typical procedure. 4-(3-Pyiidylmethyi)oxazolidme-Z5-dione hydrochloride 1194 [877] A suspension of triply recrystallized a,N-carbobenzoxy-) - 3-pyridyl)-DL-alanine 1193 (2.92 g, 9.7 mmol) in dry dioxane (50 mL) was treated, in a drybox and with rapid stirring, with a solution of PCI5 (3.06 g, 14.7 mmol) in dioxane (125 mL). After a few minutes, a dear solution was transiently formed, which then became cloudy once more. After about 2 h, precipitation began. After about 6 h, the precipitate was collected by filtration, stirred overnight with dry diethyl ether or chloroform to remove ocduded PCI5, filtered once more, and dried to yield 2.05 g (92.4%) of 4-(3-pyridylmethyl)oxazolidine-2,5-dione hydrochloride 1194. 

Typical procedure for the synthesis of t-valine N-carboxyanhydride, (2S)-4-isopropyl-oxazolidine-2,S-dione 1205 [887, 890] L-Valine (12.9 g, 0.11 mol) and activated charcoal (0.5 g) were suspended in anhydrous THF (100 mL), and to the suspension was added diphosgene (10.0 mL, 0.083 mol). The temperature was gradually increased to 60 °C, and the mixture was maintained at this temperature for 1 h. Excess phosgene was then removed by purging with nitrogen and the suspension was filtered through Celite. The yellow filtrate was concentrated in vacuo (<40 °C). Addition of pentane (ca. 500 mL) gave crystals of L-valine NCA, which were recrystallized twice from diethyl ether/pentane (14.32 g, 91%). 

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