Isophytol

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). 

The all-rac forms of P-, y-, and 5-tocopherols can be synthesized using the same condensation reaction as used for i7//-n7iC-a-tocopherol. To synthesize i7//-n7iC-P-tocopherol, 2,5-dimethylhydroquinone instead of trimethyUiydroquinone is condensed with isophytol. For all-rac- - and 5-tocopherol, 2,3-dimethylhydroqiiinone and methyUiydroquinone are used, respectively. 

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). 

CgH 02 626-19-7) see Montelukast sodium isophthaloyl chloride (C8H4CI2O2, 99-63-8) see Ditophal isophytol... 

The strong Bronstedt acid nature of some hexacoordinated phosphorus derivatives, [7",H ] (Et20)4 in particular, was recently used within the context of an industrial application [36]. The conjugated acid of tris(oxalato)phosphate anion 7 was found to effectively catalyze the ring-forming reaction of trimethyl-hydroquinone 63 with isophytol 64 to give (all rac)-a-tocopherol 65 (ethylene-carbonate/heptane 1 1,100 °C, 90%, Scheme 19). This process is particularly... 

An enantioselective hydrogenation of this type is also of interest in the production of a-tocopherol (vitamin E). Totally synthetic a-tocopherol can be made in racemic form from 2,3,5-trimethylhydroquinone and racemic isophytol. The product made in this way is a mixture of all eight possible stereoisomers. 

Partial hydrogenation of acetylenic compounds bearing a functional group such as a double bond has also been studied in relation to the preparation of important vitamins and fragrances. For example, selective hydrogenation of the triple bond of acetylenic alcohols and the double bond of olefin alcohols (linalol, isophytol) was performed with Pd colloids, as well as with bimetallic nanoparticles Pd/Au, Pd/Pt or Pd/Zn stabilized by a block copolymer (polystyrene-poly-4-vinylpyridine) (Scheme 9.8). The best activity (TOF 49.2 s 1) and selectivity (>99.5%) were obtained in toluene with Pd/Pt bimetallic catalyst due to the influence of the modifying metal [87, 88]. 

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). 

Addition of Active C-H Compounds to Dienes the Rhone-Poulenc Process for Geranylacetone - Geranylacetone is a precursor of isophytol, a key intermediate in the manufacture of vitamine E (tocopherol) (see Figure 16), the world market of which is 10 000 t/a at a price of 25-30 /kg tocopherylacetate.54... 

The direct formation of racemic a-tocopherol from trimethylhydroquinone and isophytol occurs at low temperature in the presence of boron trifluoride or aluminum chloride (71JOC2910). It is important that the solvent should not be able to complex with the Lewis acid rather, it is the phenol-catalyst complex which is alkylated. 

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). 

Ih the mid-1950 s, Hoffmann La-Roche offered synthetic linalool and its esters to the fragrance industry (5). This was another revolutionary step in the replacement of natural products with synthetics. Linalool was an intermediate in Roche s manufacture of synthetic isophytol for Vitamin E. For several years perfumers were reluctant to use chemically pure synthetic linalool and its esters in place of materials isolated from essential oils. Finally, economics prevailed and today the amount of synthetic linalool and its esters used far exceeds the traditional "linalool rich" essential oils. 

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>. 

A significant improvement in this technology was the discovery that BF -etherate could be substituted as a condensation catalyst in place of oxaHc acid (qv). Owing to the fact that oxalate esters of isophytol did not form, this substitution reduced the formation of undesired phytadiene by-products. A second notable advance was the use of l-acet5i-2-meth5i-1,4-naphthoquinone as starting material for the condensation. In addition to phytadiene, a... 

In practice, a-tocopherol (rac-1) is industrially produced on a large scale by an acid-catalyzed reaction of trimethyl hydroquinone (3) with all-rac-isophytol (4) as a mixture of all eight possible stereoisomers." ... 

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],... 

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