Iodine → Retinoic Acid

Beteiligte Stoffe

Reaktionsschritte

In general, a convergent approach, involving stereospecific coupling of the appropriate C15 (synthesized from β-ionone) and C5 synthons, has been utilized. (however, a linear sequence comprising of seven steps, starting from β-ionone, has also been described; J Org. Chem. 54, 2620-2628, 1989). For example, Patternden and Weedon, J. Chem. Soc.(C), 1984-97 (1968) have disclosed a procedure for the preparation of 13-cis retinoic acid by reacting a C15-triarylphosphonium salt (Wittig salt) and a C5-butenolide in diethylether to produce an isomeric mixture (of the cis and trans isomers at C-11 double bond) of 13-cis retinoic acid in 66-75% yield; the desired 11-trans-13-cis content is only about 36% and the rest being the corresponding 11,13-di cis isomer. Selective isomerization of the 11-cis double bond in the presence of 13-cis double bond proved extremely difficult to accomplish. A great deal of effort has been directed to affect selective isomerization of 11-cis double bond (without isomerizing the 13-cis double bond) in 11,13-di cis retinoic acid. The methods include photoisomerisation by using either iodine (J. Chem. Soc. (C) 1982, 1968), transition metal catalysts (U.S. Pat. No. 4,556,518) or photosensitizers such as erythrosin B, rose Bengal etc. (U.S. Pat. No. 5,424,465). These processes suffer from the following limitations and for various reasons are not suitable for commercial production of isotretinoin. For example, the process for selective photoisomerization using iodine under diffused light is extremely difficult to accomplish without affecting the 13-cis double bond. This results in the generation of all trans retinoic acid (tretinoin) as a major impurity in isotretinoin produced by this process. Although, U.S. Pat. No. 5,424,465 describe that use of photosensitizers enhances selectivity of photoisomerisation of C11-cis double bond, no data, however, is provided for the extent of tretinoin formation in this process.

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