Vitamin A intermediates

The major feedstocks in the modern routes to key vitamin A intermediates are butadiene, isobutene and formaldehyde. 

Vitamin A is widely used as a pharmaceutical and a food and feed additive. Scale 

Two key intermediates in the production of vitamin A are citral and the so-called C5 aldehyde. In the modem routes to these intermediates, developed by BASF and Hoffmann-La Roche, catalytic technologies are used (see Fig. 2.29 and 2.30). Thus, in the synthesis of citral, the key intermediate is 2-methyl-l-butene-4-ol, formed by acid-catalyzed condensation of isobutene with formaldehyde. Air oxidation of this alcohol over a silver catalyst at 500°C (the same catalyst as is used for the oxidation of methanol to formaldehyde) affords the corresponding aldehyde. Isomerization of 2-methyl-l-butene-4-ol over a palladium-on-charcoal catalyst affords 2-methyl-2-butene-4-ol. The latter is then reacted with the aldehyde from the oxidation step to form an enol ether. Thermal Claisen rearrangement of the enol ether gives citral (see Fig. 2.29). 

The C5 aldehyde intermediate is produced from butadiene via catalytic oxidative acetoxylation followed by rhodium-catalyzed hydroformylation (see Fig. 2.30). Two variations on this theme have been described. In the Hoffmann-La-Roche process a mixture of butadiene, acetic acid and air is passed over a palladium/tellurium catalyst. The product is a mixture of cis- and frans-l,4-diacetoxy-2-butene. The latter is then subjected to hydroformylation with a conventional catalyst, RhH(CO)(Ph3P)3, that has been pretreated with sodium borohydride. When the aldehyde product is heated with a catalytic amount of p-toluenesulphonic acid, acetic acid is eliminated to form an unsaturated aldehyde. Treatment with a palladium-on-charcoal catalyst causes the double bond to isomerize, forming the desired Cs-aldehyde intermediate. 

In the BASF process the 1,2-diacetate is the substrate for the hydroformylation step. It can be prepared either directly via oxidative acetoxylation of butadiene using a selenium catalyst or via PtCl4-catalyzed isomerization of the 1,4-diacetate (see above). The latter reaction affords the 1,2-diacetate in 95% yield. The hydroformylation step is carried out with a rhodium catalyst without phosphine ligands since the branched aldehyde is the desired product (phosphine ligands promote the formation of linear aldehydes). Relatively high pressures and temperatures are used and the desired branched aldehyde predominates. The product mixture is then treated with sodium acetate in acetic acid to effect selective elimination of acetic acid from the branched aldehyde, giving the desired C5 aldehyde. 

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In the BASF synthesis, a Wittig reaction between two moles of phosphonium salt (vitamin A intermediate (24)) and C q dialdehyde (48) is the important synthetic step (9,28,29). Thermal isomerization affords all /ra/ j -P-carotene (Fig. 11). In an alternative preparation by Roche, vitamin A process streams can be used and in this scheme, retinol is carefully oxidized to retinal, and a second portion is converted to the C2Q phosphonium salt (49). These two halves are united using standard Wittig chemistry (8) (Fig. 12). 

The same complex functions as the catalyst in the Rhone-Poulenc process (Mercier and Chabardes, 1994) for the manufacture of the vitamin A intermediate geranylacetone, via reaction of myrcene with methylacetoacetate in a biphasic system (Fig. 2.28). 

An example of a large scale application of this concept is the Ruhrchemie/ Rhone Poulenc process for the hydroformylation of propylene to n-butanal, which employs a water-soluble rhodium(I) complex of trisulfonated triphenyl-phosphine (tppts) as the catalyst [103]. The same complex also functions as the catalyst in the Rhone Poulenc process for the manufacture of the vitamin A intermediate, geranylacetone, via reaction of myrcene with methyl acetoacetate in an aqueous biphasic system (Fig. 1.35) [104]. 

For example, hydrogenation of a- and/or / -pinene, over nickel or palladium catalysts, affords ds-pinane. Autoxidation of ds-pinane (in the absence of a catalyst) gives the tertiary hydroperoxide (see Fig. 8.42) which is hydrogenated to the corresponding alcohol. Thermal rearrangement of the latter affords the important flavor and fragrance and vitamin A intermediate, linalool (Fig. 8.42) [213]. 

Chirazyme L2-C2 (CAL-B) proved to be a very useful enzyme for the development of an acylation process for the large-scale production of vitamin A (retinol, 91) at Roche (Scheme 27) [90,91]. In the plant process of vitamin A, intermediate 88 is partially acylated and then subjected to acid-catalyzed dehydration and isomerization to yield the vitamin A ester 90 via acetate 89. Contrary to the chemical acylation, an enzymatic approach allowed for a highly selective monoacylation of 88, and Chirazyme L2-C2 showed a very high conversion rate at 30% (w/w) substrate concentration. A first continuous process on the laboratory scale was set up with a 15 ml fixed-bed reactor containing 5.0-8.0 g of immobilized biocatalyst 4.9 kg of 89 was synthesized within 100 days in 99% yield and with 97% selectivity for the primary hydroxyl group. The laboratory process was implemented in a miniplant (120 g of biocatalyst), which could convert 1.4 kg of 88 into 1.6 kg 89 per day. After 74 days the conversion efficiency was still 99.4%. Further development of this transformation led to a modified process, which uses Thermomyces lanuginosus lipase immobilized on Accurel MPlOOl for the continuous production of 89 [92]. 

Base lb has recently been used in the synthesis of vitamin A [117]. Thus the product in Eq. (9) was reported in a patent [117a] and those in Eqs. (10) and (11) were described in recent work from our laboratories [117b]. Although lb was found to be less effective than DBN or DBU in removing HBr from the mixture of vitamin A intermediates shown in Eqs. (10) and (11) when the dehydrohalo-genation was carried out in refluxing benzene, lb was faster than DBN or DBU in acetonitrile. 

The synthesis of the monoacetal 24 (Scheme 10) starts from the key vitamin A intermediate 73. Acetalization with 2,2-dimethylpropane-l,3-diol furnished the acetoxyacetal 95 in high yield. Transesterification of 95 with methanol in the presence of a catalytic amount of sodium methoxide, followed by work-up and distillation, provided the hydroxyacetal 96 in nearly quantitative yield. 

Storage Refrigerate store under nitrogen store in well-ventilated area away from incompat. substances keep away from heat, sparks, flame Uses Chlorinated solvent solvent for hard resins, nitrocellulose reactive chloro intermediate for the modification of amines, alcohols, and carboxylic acids C3-building block mfg. of photographic and Zapon lacquer cement for celluloid binder for water colors in determination of Vitamin A intermediate in organic synthesis in paints, varnishes, lacquers Regulatory Canada DSL... 

Chloroacetate esters are usually made by removing water from a mixture of chloroacetic acid and the corresponding alcohol. Reaction of alcohol with chloroacetyl chloride is an anhydrous process which Hberates HCl. Chloroacetic acid will react with olefins in the presence of a catalyst to yield chloroacetate esters. Dichloroacetic and trichloroacetic acid esters are also known. These esters are usehil in synthesis. They are more reactive than the parent acids. Ethyl chloroacetate can be converted to sodium fluoroacetate by reaction with potassium fluoride (see Fluorine compounds, organic). Both methyl and ethyl chloroacetate are used as agricultural and pharmaceutical intermediates, specialty solvents, flavors, and fragrances. Methyl chloroacetate and P ionone undergo a Dar2ens reaction to form an intermediate in the synthesis of Vitamin A. Reaction of methyl chloroacetate with ammonia produces chloroacetamide [79-07-2] C2H ClNO (53). 

Vitamins. The preparation of heat-sensitive natural and synthetic vitamins (qv) involves solvent extraction. Natural vitamins A and D are extracted from fish Hver oils and vitamin E from vegetable oils (qv) Hquid propane [74-98-6] is the solvent. In the synthetic processes for vitamins A, B, C, and E, solvent extraction is generally used either in the separation steps for intermediates or in the final purification. 

Methyl vinyl ketone is used as a comonomer in photodegradable plastics, and is an intermediate in the synthesis of steroids and vitamin A. It is highly toxic and faciUties handling over a threshold of 100 lbs (45.5 kg) are subject to special OSHA documentation regulations (273). 

Rearrangement of dehydrolinalool (4) using vanadate catalysts produces citral (5), an intermediate for Vitamin A synthesis as well as an important flavor and fragrance material (37). Isomerization of the dehydrolinalyl acetate (6) in the presence of copper salts in acetic acid followed by saponification of the acetate also gives citral (38,39). Further improvement in the catalyst system has greatly improved the yield to 85—90% (40,41). 

Petrochemical-based methods of citral manufacture are very important for the large-scale manufacture of Vitamin A and carotenoids. Dehydrolinalool and its acetate are both made from the important intermediate, P-methyUieptenone. 

Vitamin A acetate [11098-51-4] (2) is the commercially significant form of the vitamin and is mainly produced by Hoffmann-La Roche, BASF, and Rhc ne-Poulenc (Fig. 4). AH of these processes have P ionone (18) as their key intermediate and in this regard are based on work performed in the 1940s... 

The largest industrial use of LiC2H is in the production of vitamin A, where it effects ethynyl-ation of methyl vinyl ketone to produce a key tertiary carbinol intermediate. The acetylides and dicarbides of the other alkali metals are prepared similarly. It is not always necessary to prepare this type of compound in liquid ammonia and, indeed, further substitution to give the bright red perlithiopropyne Li4C3 can be effected in hexane under reflux ... 

Carotene cleavage enzymes — Two pathways have been described for P-carotene conversion to vitamin A (central and eccentric cleavage pathways) and reviewed recently. The major pathway is the central cleavage catalyzed by a cytosolic enzyme, p-carotene 15,15-oxygenase (BCO EC 1.13.1.21 or EC 1.14.99.36), which cleaves p-carotene at its central double bond (15,15 ) to form retinal. Two enzymatic mechanisms have been proposed (1) a dioxygenase reaction (EC 1.13.11.21) that requires O2 and yields a dioxetane as an intermediate and (2) a monooxygenase reaction (EC 1.14.99.36) that requires two oxygen atoms from two different sources (O2 and H2O) and yields an epoxide as an intermediate. ... 

Recently, a study of this rearrangement has been repeated and extended in order to determine the influence of a- and y-substitution on the position of the 68-69 equilibrium in the presence of silica, and the utility of this reaction for a novel and convenient synthesis of highly substituted a, 8-unsaturated ketones, by subsequent treatment with CuClj in methanol-water . An ion-pair mechanism can also be suggested for the facile rearrangement of sulfone 70 to 71, a key intermediate in the Hoffmann-La Roche Sulfone Route to Vitamin A . 

The synthetic utility of the remarkably facile and efficient [2,3]-sigmatropic rearrangement of propargylic sulfenates has been further demonstrated in a variety of preparations and interesting reactions of allenyl sulfoxides , including the preparation of vinylallenes " which are useful intermediates in organic synthesis in general and natural polyenes, such as Vitamins A and D, in particular Two typical examples, taken... 

An intere.sting example in the context of waste minimization is the manufacture of the vitamin K intermediate, menadione. Traditionally it was produced by stoichiometric oxidation of 2-methylnaphthalene with chromium trioxide (Eqn. (8)), which generates 18 kg of solid, chromium containing waste per kg of menadione. Catalytic alternatives have been reported, but selectivities tend to be rather low owing to competing oxidation of the second aromatic ring (the. selectivity in the classical process is only 50-60%). The best results were obtained with a heteropolyanion as catalyst and O2 as the oxidant (Kozhevnikov, 1993). 

Industrial synthesis of vitamin A (Hoffman-La-Roche) goes through partial hydrogenation of an enyne (equation 161)277. A number of syntheses of pheromones, where the reduction of an enyne to a diene is the key step, have been devised. A few selected examples are given in Table 29278. During the total synthesis of endiandric acids, Nico-laou employed hydrogenation of a polyenyne intermediate with a Lindlar catalyst to generate an intermediate which underwent symmetry-allowed cyclizations to result in the natural product (equation 162)279. 

Four deuteriated retinols, 26-29, with 3 to 5 deuterium atoms have been synthesized29 for metabolism of vitamin A studies in humans30. Deuterium has been introduced into appropriate intermediates, used in the reaction scheme shown in equation 12, by base-catalysed exchange with 2H20 or perdeuterioacetone. The numbering system for retinol (vitamin A alcohol) is shown in equation 12. 

In that way, one of the principal approaches to the preparation of vitamin A derivatives consists of a selection of starting and/or intermediate structures which cannot be rearranged. In contrast, the object of another approach is to search the conditions of the reverse transformation, i.e. a rearrangement of retro-structures to the desirable ionylidene systems. Most frequently, basic reagents (e.g. NaOH, KOH, AcOK, pyridine, AlkONa etc.) are used for this purpose but an application of acid reagents is also known146. 

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