Method for synthesizing alcoholic hydroxyl fluorine derivatives

Abstract

The invention discloses a method for synthesizing alcoholic hydroxyl group fluoro derivatives, which belongs to the technical field of chemosynthesis. In the presence of organic amine and organic solvent, PBSF and TBAT are jointly used as fluorination reagents and subjected to fluorination with hydroxyl derivatives, so as to obtain the alcoholic hydroxyl group fluoro derivatives. The synthesis method has the advantages of greatly reducing and eliminating byproducts, reducing the amount of the TBAT to an equivalent below 1.2, completely inverting the configuration of the fluorination of chiral alcoholic hydroxyl under mild conditions and reducing optical isomer impurities.

Description

Technical field [0001] The invention relates to a synthetic method, in particular to a new synthetic method in which PBSF and TBAT are used in combination as a fluorinating reagent to fluorinate alcoholic hydroxyl groups. Background technique [0002] Fluorine elements in drugs usually exist in the form of carbon-fluorine bonds. In many contemporary therapeutic fields, powerful and low-toxic drugs contain fluorine elements, such as norfloxacin, ciprofloxacin, Sitafloxacin, Clofarabine, fludropine, etc. This is due to the unique biological activity of the carbon-fluorine bond (Welch, JTTetrehedron 1987, 43, 3123). One of the most direct methods of carbon-fluorine bond formation is to replace alcoholic hydroxyl groups with fluorine (Yoneda, N. Tetrahedron 1991, 47, 5329). Early developed fluorinated reagents are SF 4 (Wang, CLJOrg. React. 1985, 34, 319), Olah reagent (Olah, GANojima, M.; Kerekes, IJAm. Chem. Soc. 1974, 96, 925) and its analogs [a). Olah , GA et al. Synthesis 1993, ...

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Problems solved by technology

The early developed fluorinated reagents are SF 4 (Wang, C.L.J.Org.React.1985, 34, 319), Olah's reagent (Olah, G.A.Nojima, M.; Kerekes, I.J.Am.Chem.Soc.1974, 96, 925) and analogs [a).Olah , G.A.et al.Synthesis 1993,693; b).Yoneda, N.et al.Chem.Lett.1983,1135; c).Wiechert, D.et al.J.Am.Chem.Soc.1997,119, 12665], the complex of ether and hydrogen fluoride (Olah, G.A.et al.J.Am.Chem.Soc.2002,124,7728) fluorocarbon amine reagent [a).Takaoka, A.et al.Bull.Chem. Soc.Jpn.1979,52,3377;b).Dmowski,W et al.J.Fluorine Chem.1983,23,219;c).Petrov,V.A.et al.J.Fluorine Chem.2001,109,25] , DFI (Hayashi, H et al. Chem. Commun. 2002, 1618), IF 5 / Et 3 N.3HF (Yoneda, N.; Fukuhara, T. Chem. Lett. 2001, 222), DAST (Middleton, W. J. J. Org. Chem. 1975, 40, 574) and its analog BAST (Lal, G. S. et al. J. Org.Chem.1999, 64, 7048). These reagents all have these problems or some of these problems: highly toxic, dangerous, unstable, difficult to operate, need harsh reaction conditions, strong corrosion, low reaction yield, difficult to prepare, expensive etc.

TBAT, as a fluorinated reagent, needs to convert the alcoholic hydroxyl group into a sulfonate (such as: mesylate, trifluorosulfonate, p-toluenesulfonate), and reflux in acetonitrile to complete the reaction; its disadvantages include: A very excessive amount of TBAT is required, about 4 equivalents of TBAT are required for primary alcohols, about 6 equivalents of TBAT are required for secondary alcohols, and there are a considerable amount of elimination products, mainly elimination products for tertiary alcohols, with only a small amount of fluorinated products; For the fluorinated products of chiral alcohols, there are some isomer impurities with non-inverted configurations (Picher, A.S. et al J.Am.Chem.Soc.1995, 117, 5166)

These disadvantages severely limit its application as a fluorinated reagent

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