A cis-4-fluoro-L-proline derivative can be prepared from a trans-4-hydroxy-L-proline derivative through fluorination of its hydroxyl group at the 4-position. However, conventional fluorination techniques have posed various problems, as explained below.
The first method for fluorination is a method which uses diethylaminosulfur trifluoride (DAST). This method provides a target product in good yield, but is unsuitable for industrial use because DAST is highly toxic and less heat stable, as well as being explosive and expensive (Luc Demange et al., Tetrahedron Lett., 39, 1169 (1998)).
The second method is a method in which the hydroxyl group at the 4-position is converted into a leaving group and then into a fluoro group (G. Giardina et al., Synlett, 1, 55 (1995)). This method is of limited practical use because the yield of a target product is reduced as a result of olefin generation caused by β-elimination of the leaving group.
The third method is a method which uses N,N-diethyl-N-(1,1,2,3,3,3-hexafluoropropyl)amine (hereinafter referred to as “Ishikawa reagent”). This method is considered to be excellent in that it has a reduced risk of explosion, is available at low cost and enables the introduction of a fluoro group in a single step. However, there is a problem of reduced yield of a target compound because hydrogen fluoride generated during the reaction causes not only erosion of reaction vessels, but also decomposition of starting materials and reaction products. Moreover, particularly in the case of using a urethane-type protecting group which is widely used as a protecting group for an amino group in an α-amino acid, this protecting group will be easily decomposed by the action of hydrogen fluoride and hence requires the limited reaction conditions (e.g., at low temperature over a long period of time), thus failing to produce satisfactory results in terms of yield, etc.