Isophytol synthesis

The synthesis of the side chain started from acetone and followed the pattern of the isophytol synthesis in Pig. 9. Cis-irana isomerism at the newly formed double bonds must be taken into account. Geranylacetone was sep-... 

Geranyl acetone is an important intermediate in the synthesis of isophytol [505-32-8], famesol [106-28-5], and neroHdol [40716-66-3]. Isophytol is used in the manufacture of Vitamin E. 

Phytol [505-06-5] (111) and isophytol [150-86-7] (112) are important intermediates used in commercial synthesis of Vitamins E and K. There is a variety of synthetic methods for their manufacture. Chlorophyll [479-61-8] is a phytyl ester. 

Although all four tocopherols have been synthesized as their all-rac forms, the commercially significant form of tocopherol is i7//-n7i a-tocopheryl acetate. The commercial processes ia use are based on the work reported by several groups ia 1938 (15—17). These processes utilize a Friedel-Crafts-type condensation of 2,3,5-trimethylhydroquinone with either phytol (16), a phytyl haUde (7,16,17), or phytadiene (7). The principal synthesis (Fig. 3) ia current commercial use iavolves condensation of 2,3,5-trimethylhydroquiQone (13) with synthetic isophytol (14) ia an iaert solvent, such as benzene or hexane, with an acid catalyst, such as ziac chloride, boron trifluoride, or orthoboric acid/oxaUc acid (7,8,18) to give the all-rac-acetate ester (15b) by reaction with acetic anhydride. Purification of tocopheryl acetate is readily accompHshed by high vacuum molecular distillation and rectification (<1 mm Hg) to achieve the required USP standard. 

Fig. 3. Synthesis via trimethyUiydroquinone [700-13-0] (TMHQ) (13) and isophytol [505-32-8] (14) of a-tocopherol (15a) and a-tocopherol acetate (15b).

The isophytol side chain can be synthesized from pseudoionone (Fig. 5) using chemistry similar to that used in the vitamin A synthesis (9). Hydrogenation of pseudoionone (20) yields hexahydropseudoionone (21) which can be reacted with a metal acetyUde to give the acetylenic alcohol (22). Rearrangement of the adduct of (22) with isopropenyknethyl ether yields, initially, the aHenic ketone (23) which is further transformed to the C g-ketone (24). After reduction of (24), the saturated ketone (25) is treated with a second mole of metal acetyUde. The acetylenic alcohol (26) formed is then partially hydrogenated to give isophytol (14). 

As practiced by Hoffmann-La Roche, the commercial synthesis of vitamin is outlined ia Figure 1. Oxidation of 2-methylnaphthalene (4) yields menadione (3). Catalytic reduction to the naphthohydroquinone (5) is followed by reaction with a ben2oating reagent to yield the bis-benzoate (6). Selective deprotection yields the less hindered ben2oate (7). Condensation of isophytol (8) (see Vitamins, vitamins) with (7) under acid-cataly2ed conditions yields the coupled product (9). Saponification followed by an air oxidation yields vitamin (1) (29). 

Isophthaloyl chlorides, 19 715 Isophytol, 24 502, 550 Isopolytungstate compounds structures of, 25 383-384 Iso prefix, 13 594-595 Isoprene, 24 501 Alfrey-Price parameters, 7 617t block copolymer synthesis, 7 647t butyl rubber polymers, 4 433 commercial block copolymers, 7 648t glass transition and melting... 

This first example of a Bi(OTf)3-catalyzed Friedel-Crafts alkylation originated in the following procedures, including benzylations of 2,4-pentanediones or hydroarylation and hydroalkylation reactions. A related procedure was simultaneously developed by Bonrath et al. [39]. The authors utilized Bi(OTf)3 in the synthesis of (all-rac)-a-tocopherol (Vitamin E) [39], Besides rare earth metal triflates, such as Ga(OTf)3, Hf(OTf)3, Sc(OTf)3 and Gd(OTf)3, Bi(OTf)3 was shown to be the most efficient catalyst for the Friedel-Crafts-type reaction between trimethylhydroquinone acetate 10b and isophytols 11a, b. With only 0.02 mol% Bi(OTf)3 (substrate to catalyst ratio 5,000 1) the desired a-tocopherols 12a and 12b were isolated in excellent yields (Scheme 10). 

H3PW12O40 and H4SiWi204o are also active for the condensation of isophytol and l-acetoxy-4-hydroxy-2-methylnaphthalene, which is a key step in the synthesis of vitamin K (2-methyl-3-phytyl-1,4-naphthoquinone) [Eq. (43)] heteropolyacids are approximately 50 times more active than ZnCl2 (362). 

The synthesis of Vitamin E, that is, a-tocopherol (5,7,8-trimethyltocol) in the past has been accomplished primarily by reacting trimethylhydroquinone (TMHQ) with isophytol (3,7,ll,15-tetramethylhexadec-l-en-3-ol) or phytol (3,7,ll,15-tetramethylhexadec-2-en-l-ol) in a condensation reaction. The reaction is well known and has been practiced for many years (Stalla-Bourdillon, Ind. Chim. Belg., 35, 13 (1970) "The Vitamins" Vol. 5, pages 168-223, Academic Press, New York, 1967). 

A complex multistep synthesis of the 8-CD3 analogue of 5-tocopherol has been described <03EJ02840>. The super Lewis acid, Me3Si[C6FsCTf2], is an effective catalyst for the regioselective condensation between trimethylhydroquinone and isophytol that yields ( )-a-tocopherol <03AG(E)5731>. 

Based on these biological data, two commercial forms of a-tocopherol (or their more stable acetate derivatives) are currently being produced by independent approaches [7, 8], Totally synthetic vitamin E, which is an equimolar mixture of all eight stereoisomers of a-tocopherol, is produced at a rate of over 25000 tons per year for the application in feed, food, and the pharma industry. The large-scale industrial synthesis of (all-rac)-a-tocopherol uses 2,3,5-trimethylhydroquinone (11) as the aromatic building block and the C2o compound isophytol (12). The acid-catalyzed condensation reaction in the last step delivers (all-rac)-3 (Fig. 2) [21-25],... 

A variety of methods is now available for the synthesis (artificial production) of the tocopherols. In the most commonly used procedure, 2,3,5-trimethylhydroquinone is reacted with isophytol over one of many possible catalysts. A small amount of the vitamin is still obtained from natural sources, usually as the by-product in the treatment of one of its natural sources. 

Racemic isophytol was synthesized from lemon grass oil, or totally from acetone. In the synthesis of isophytol from lemon grass oil (Fig. 9) its main constituent, citral, is condensed with acetone to give pseudoionone. Hydrogenation leads to hexahydropseudoionone. Lengthening of the chain by an isoprene unit is effected by condensation of this ketone with sodium acetylide in liquid ammonia followed by partial hydrogenation of the triple... 

Fig. 10. Synthesis of isophytol from acetone. 1, Sodium acetylide in liquid ammonia S, partial hydrogenation S, phosphorus tribromide followed by acetoacetate synthesis, or condensation with diketene followed by pyrolysis 4, hydrogenation.

A more economical synthesis of isophytol using diketene was devised and developed to a manufacturing procedure by Kimel et of. (1958) of Hoff-mann-La Roche Inc. in Nutley, New Jersey. In Kimers procedure, methyl-butenol and its isoprenologs are condensed with diketene to give its acetoacetate, from which on pyrolysis methylheptenone and its isoprenologs are formed in high yields under evolution of CO, (cf. Kimel and Cope, 1943). 

Linalool can be converted to geranyl acetone by the Carroll reaction (156). After transesterification with ethyl acetoacetate, the intermediate ester thermally rearranges with loss of carbon dioxide. Linalool can also be converted to geranyl acetone by reaction with methyl isopropenyl ether. The linalyl isopropenyl ether rearranges to give geranyl acetone. Geranyl acetone is an important intermediate in the synthesis of isophytol [505-32-8], famesol [106-28-5], and nerolidol [40716-66-3]. Isophytol is used in the manufacture of Vitamin E and thus linalool is a key intermediate in the synthesis of the latter. All of these reactions are shown in Fig. 8.55 in the section on nerolidol. 

As described above, phytol (301) and isophytol (302) can be manufactured from gera-nylacetone in a sequence exactly analogous to those for the production of geraniol and linalool from methylheptenone. Geranylacetone, in turn, can be obtained from either myr-cene or linalool. Both phytol and isophytol are important as intermediates in the synthesis of vitamins E and K and isophytol is used as a diluent in higher price fragrances (82). 

Figure 6.18 Schematical Synthesis of (AII-rac)-a-Tocopherol (Vitamin E) via Two-Step Friedel-Crafts Alkylation-Cyclization of 2,3,6-Trimethylhydroquinone (TMHQ) with Isophytol (IP).

The industrial synthesis of this valuable compound is based on the condensation of 2,3,6-trimethylhydroquinone (TMHQ) with isophytol (IP), which proceeds through consecutive Friedel-Crafts alkylation-cyclization (Figure 6.18) steps [91] in the presence of ZnClj/HCl as catalyst [92],... 

Sn(OTf) -MCM-41 and Sn(OTf) ,-UVM-7 solids have been tested as catalysts for the acylation of aromatic sulfonamides, in the synthesis of (DL)-[a]-tocopherol through the condensation of 2,3,6-trimethylhydroquinone with isophytol (Equation (8.56)) and for the transesterihcation of sunflower oil [109-112]. The acylation of aromatic sulfonamides was possible on these materials with a very high atom economy using acetic acid as the acylat-ing agent. These catalysts were also found active for the synthesis of 4,4 -methylenediani-line (a key intermediate for the production of polyurethanes) from aniline and 4-aminoben-zyl alcohol [74]. 

Table 3.2 shows some results of tocopherol synthesis obtained with different MgF2 based catalysts. Both crystalline MgF2 (entry 1) and HS-MgF2 prepared with very little or no water (entries 7 and 8) were not at all active, even after prolonged reaction time. As crystalline MgF2 exhibits almost no acidity its inactivity was to be expected. On the other hand, a HS-MgF2 catalyst prepared with 71% aqueous HF resulted in total conversion of isophytol and almost 100% selectivity to (all-rac)-[a]-tocopherol (entry 6). The activities of the catalysts do not correspond to their respective numbers of acid centres (Table 3.2). Likewise, the F MAS NMR spectra do not correspond to the activity.

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