3-Hydroxytetrahydrofuran (3-OH THF) is a colorless liquid with a normal boiling point of 179 °C and boiling at 88−89 °C at 17 mmHg, with density (1.087 g/cm3 at 19 °C). 3-OH THF is a useful pharmaceutical intermediate. The enantiopure (absolute configuration S) version of this compound is an intermediate to launched retroviral drugs.Venkata Mandava, et al., "Preparation of fosamprenavir calcium" U.S. Pat. Appl., 20110224443 (2011)
Synthesis 3-Hydroxytetrahydrofuran was prepared in 1909 by Pariselle via cyclization and hydrolysis of 3,4-Dibromo-1-methoxybutane. Chiral 3-hydroxytetrahydrofuran (both (S) – and (R)-forms) has been synthesized in high enantiomeric purity from (S)- and (R)-1,2,4-butanetriol, respectively, obtained from chiral feedstocks. Thus, the chiral (S)-1,2,4-butanetriol intermediate was cyclized to chiral (S)-3-hydroxytetrahydrofuran in the presence of p-toluenesulfonic acid (PTSA) catalyst at temperatures of 180−220 °C. Similarly, (S)-3-hydroxytetrahydrofuran was prepared in 95.8% optical purity from L-malic acid via an esterification-reduction-cyclodehydration sequence. 3-hydroxytetrahydrofuran has been synthesized via hydroboration of 2,3- and 2,5-dihydrofuran employing various borane reagents and chiral 3-hydroxytetrahydrofurans have also been prepared by catalytic asymmetric hydroboration of 2,3- and 2,5-dihydrofurans with a borane in the presence of a homogeneous chiral platinum complex, followed by oxidation.Anita Schnyder, et al., "Preparation of optically active 3-hydroxytetrahydrofurans by catalytic asymmetric hydroboration of dihydrofurans" Ger. Offen., 19807330 (1998) Racemic 3-hydroxytetrahydrofuran may be prepared in analogous fashion from racemic butanetriol, employing PTSA catalyst for the dehydrocyclization. Alternatively, 1,2,4-butanetriol may be converted to 3-hydroxytetrahydrofuran by treating with ethylene carbonate, followed by pyrolysis of the resulting carbonate ester.
Applications 3-Hydroxytetrahydrofuran is an intermediate to the AIDS drugs amprenavir and fosamprenavir. Additionally, 3-OH THF has been an intermediate to developmental drug substances, such as chemotherapy agents. For example, reaction of phosphorus pentasulfide with 3-hydroxytetrahydrofuran has been used in the synthesis of bis(O,O-di(tetrahydrofuran-3-yl)hydrogen dithiophosphate)platinum(II), a cisplatin analog.Anthony Lowe, et al., "Dithiophosphato platinum complexes for the treatment of cancers" PCT Int. Appl., 2005095425 (2005) 3-hydroxytetrahydrofuran may be converted into a range of tetrahydrofuran derivatives, many of which also serve as intermediates to compounds of pharmaceutical interest. For example, tetrahydrofuran-3-one (3-ketotetrahydrofuran) and 3-aminotetrahydrofuranLiren Jin, et al., "Process for preparation of (R)-3-aminotetrahydrofuran" Faming Zhuanli Shenqing Gongkai Shuomingshu, CN 1660829 A 20050831 (2005) have been synthesized from 3-hydroxytetrahydrofuran and used in pharmaceutical syntheses. Additionally, additive amounts (0.05-0.15 weight %) of the nitrate ester manufactured by sulfuric acid-nitric acid nitration of 3-hydoxytetrahydrofuran have been found to increase the quality (cetane number) of diesel fuel.Allen H. Filbey, "Diesel fuel composition" U.S. Pat., 4406665 (1983)
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