Retinol industrial synthesis

Since its discovery in 1909, the elucidation of its structure by Karrer in 1931 [5] and its first total synthesis [6], vitamin A has represented a challenging target molecule for chemists [7], The first industrial synthesis of retinol was performed at Hoffmann-La Roche (H-L R) [8], followed by other approaches of the Baadische Anilin- Soda Fabrik (BASF AG) [9], and Rhone-Poulenc (R-P) (today Aventis) [10]... 

Total synthesis is applied for carotenoids on a lO t scale per year. One usually starts with the cheapest carbonyl components (formaldehyde, acetone) and carbanions (acetylide, acetoacetate, cyanide, Wittig ylides) available. A typical industrial synthesis of retinol acetate (vitamin A) is outlined in Scheme 5.3,1. 

In 1935 Hamano and Kawakami (1935) characterized retinol (1) as the P-naphthoate and anthraquinone P-carboxylate. Later Baxter and Robeson (1940) were able for the first time to obtain crystalline retinyl palmitate (113) and crystalline retinol (1) from liver oils. Crystalline retinyl acetate (9) and crystalline retinyl succinate were obtained at a later date (Baxter and Robeson, 1942). These very pure compounds made possible the accurate determination of a number of physical data. In 1946 Hanze et al. (1948) synthesized pure retinyl methyl ether (571) from crystalline retinol (1), and the total synthesis of this ether was reported at the same time by Milas et al. (1948). At this time also, syntheses of retinoids were carried out by Isler and associates and led to the first industrial synthesis of retinol derivatives (Isler et al., 1947 Isler, 1950 Heilbron and Weedon, 1958 Isler, 1979). 

The acetylenic diol (8) used as an intermediate in an industrial synthesis (Isler, 1977) of retinol (1) underwent rearrangement in the presence of heavy metal ions to give the furans (53) and (54). 

In a similar manner, it proved possible to obtain the series of dehydrogenated 9Z compounds and 9Z,13Z compounds from the 9Z isomer of the Cj5 aldehyde (294). It was also possible to prepare geometric isomers of 3,4-didehydroretinol (289) on the basis of the reaction principles of Isler s industrial synthesis of retinol. The didehydro C14 aldehyde (299), which is analogous to (6), was coupled to the acetylene alcohols (300) and (7) in a conventional manner (Sch-wietereffl/., 1962a). 

In addition to these structures, other retinoids were synthesized with side chains modified by an oxygen functional group. When the C20 diol (490), a building block that is readily obtainable in an industrial synthesis of retinol (1) (Isler et al., 1949), was oxidized with manganese(IV) oxide, the ketoaldehyde (491) was obtained (Surmatis, 1972). 

The successful synthesis of (all- )-retinoic acid (3) was reported by Arens and van Dorp (van Dorp and Arens, 1946) in 1946, but almost 10 years passed before Robeson et aL (1955a) were able to prepare 13-cw-retinoic acid (17). Between 1946 and 1956, a large number of papers were published on successful syntheses of the natural C20 retinoids retinol (1), retinaldehyde (2), and retinoic acid (3), and nine industrial processes for the synthesis of vitamin A were developed during this period (Isler, 1979). 

The economically most important processes today are those of Hoffmann-La Roche and BASF. At Hoffmann-La Roche, Isler et aL developed the first industrial retinol synthesis, which was based on a reaction sequence they had used in 1947 to synthesize crystalline retinol (1) (Isler et aL, 1947) The last C—C bonding step was the Grignard reaction between the C14 aldehyde (6) and the Cg acetylene compound (7) to give carbinol (8), which was then converted to retinyl acetate (9). 

In the course of almost 50 years of synthetic retinoid chemistry up to the present time, a large number of processes for the synthesis of retinol (1) and its esters, such as retinyl acetate (9) and retinyl palmitate (113), have been developed. The most important large-scale industrial processes today are based on the work of Isler et al. at Hoffmann-La Roche, and of Pommer et al. at BASF. These two processes probably satisfy a large part of the world demand for retinol (1) (vitamin A), most of which is used for the production of animal feeds. 

The synthetic chemistry efforts in the retinoid field have been dominated for the most part by two large research groups Hoffmann-La Roche (Mayer and Isler, 1971) and Badische Anilin und Sodafabrik (BASF) (Pommer, 1960). These investigators have published numerous papers and patents as a result of industrially oriented research on the practical total synthesis of retinol and its analogs. Selected portions of this work can be adapted to the synthesis of radiolabeled retinoids. 

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