Vitamin A acetate, synthesis

Figure 3.5 Schematic representation of modular microreactor setup employed for the vitamin A acetate synthesis (1 pressure probe 2 micromixer 3 microheat exchanger 4 capillary reactor with electrical heating 5 thermal liquid inlet for heat exchanger).

Figure 3.6 Exemplary results of the study of the vitamin A acetate synthesis with an MMRS. (a) HPLC conversion and yield versus temperature 7i = T2. (b) HPLC conversion and...

Dye-Sensitized Photoisomerization. One technological appHcation of photoisomerization is in the synthesis of vitamin A. In a mixture of vitamin A acetate (all-trans stmcture) and the 11-cis isomer (23), sensitized photoisomerization of the 11-cis to the all-trans molecule occurs using zinc tetraphenylporphyrin, chlorophyU, hematoporphyrin, rose bengal, or erythrosin as sensitizers (73). Another photoisomerization is reported to be responsible for dye laser mode-locking (74). In this example, one metastable isomer of an oxadicarbocyanine dye was formed during flashlamp excitation, and it was the isomer that exhibited mode-locking characteristics. 

The Wittig process for the synthesis of vitamin A acetate is carried out on the industrial scale and produces a mixture of the all-trans and 11-cis isomers. Only the all-trans form is suitable for pharmaceutical or... 

Two patents by Takahashi et al. reported the synthesis of vitamin A via a Cio dihalogeno derivative [34,35]. In one procedure the halogenodiene was prepared by bromination of 3,7-dimethyl-2,5,7-octatrien-1-yl acetate. Addition of the latter and /BuOK in DMF to the Cio sulfone provided the retinol sulfone (34%). Again, double elimination (MeOK), gave vitamin A acetate, Fig. (13). 

Tanaka et al. reported a synthesis of vitamin A derivatives from C15 phosphonates [85]. Vitamin A acetate was prepared in 92% yield by reaction of the C15 phosphonate with 2-methyl-4-acetoxy-2-butenal, Fig. (47). 

It has been assumed so far that the sensitizer acts by an energy-transfer mechanism, but in some cases other modes of interaction may occur. It is possible that electron transfer takes place to give the radical anion or the radical cation of the alkene, which is the species that subsequently isomerizes. This is likely to be the case in the chlorophyll-sensitized isomerization of vitamin A acetate, which is used commercially to obtain the required all-trans isomer 12.8) from the mixture of Isomers resulting from the synthesis. Unlike triplet-sensitized reactions, electron-transfer isomerizations frequently lead to a predominance of the most thermodynamically stable isomer. 

The EM Modular Reaction System can also be used to perform multi-step syntheses [83], For the production of pharmaceuticals, in this case for the synthesis of vitamin A, an ylid is formed from a phosphonium salt and a base in the first stage at 2 °C. In a second stage, the ylid reacts with an aldehyde at 60 °C in a flow-through capillary reactor. In a third stage the crude product is hydrolyzed at 20 °C in an additional micro mixer to form the target product vitamin A acetate, as illustrated. For the claimed reaction, no further experimental details were given. 

The synthesis of vitamin A was certainly a pioneering work in the industrial application of the Wittig reaction 6). The decisive step in this synthesis performed by the BASF, which had already established a plant for the production of vitamin A in 1971 2S4), is the Wittig olefination of vinyl-P-ionol 503 with y-formylcrotyl acetate 507 to vitamin A acetate 508. The phosphonium salt 505 is obtained by reaction of the alcohol 503 with triphenylphosphine hydrobromide 504 2S5) (Scheme 85). 

After it had been proved that the Wittig reaction was suitable, in principle, for polyene syntheses, the linking of a C5 building block with a C15 ylide (6) was chosen for the synthesis of vitamin A acetate (9). Suitable C5 building blocks, such as, for example, P-formylcrotyl acetate (8), were, of course, still unknown at that time. 

The phosphonium salt is more acidic than usual because its conjugate base, the ylide, is stabilized by resonance involving the double bonds. Therefore, methoxide ion, a weaker base than usual, can be used lo form the ylide. Reaction of the ylide with the aldehyde that has its hydroxy group protected as an ester produces vitamin A acetate. The acetate group can readily be removed to complete the synthesis of vitamin A (see Section 10.2). 

A question of regiochemistry arises with O-silylated dienolates derived from a, -unsaturated aldehydes, ketones and esters. The silylated dienolates of crotonaldehyde and its 3-methyl derivative (108) react with acetals in Lewis acid catalyzed conditions at the y-position. This high regioselectivity has been used in the synthesis of vitamin A acetate (Scheme 41). ... 

An analogous strategy allows the direct synthesis of vitamin A acetate (W) by employing the Cs-chloroacetate 11 (Scheme 3) [2]. Reaction of the anion of 7 with 11 gives 72, which is converted into 10 upon treatment with base. The acetate thus obtained consists of (all- )-(-80%) and (9Z)-isomers (-20%). The elimination reaction can best be performed by the use of potassium alkoxide in refluxing hydrocarbon solvent. 

The alkylation/elimination methodology is also applicable to synthesis of carotenoids. The basic strategies for the apo-8 -p-carotenoids [ 12] and for p,p-carotene (3) [ 13] are depicted in Schemes 10 and 11. Vitamin A acetate (10) was reacted with sodium /7-phenoxybenzene-sulphinate to give the sulphone 31. The reaction of 31 with the bromo compounds 32 and 33, respectively gave the apocarotenoic acid ester 34 and the corresponding aldehyde 482. 

Reaction between the lithiate of cyclogeranyl sulphone (25) and the aldehyde ester 43, followed by tetrahydropyranylation of the hydroxy group of the coupling product, furnishes 44. Treatment of 44 with ten equivalents of f-BuOK in refluxing f-BuOH leads to methyl retinoate (19) (all- 13Z= 1 1). The versatility of the double elimination method is highlighted by a novel synthesis of vitamin A acetate (JO) (Scheme 15) [17,18]. 

The final common intermediate for the syntheses of vitamin A and P,p-carotene (3) is the Ci4-aldehyde 23, which is obtained from p-ionone f/7) by glycidic ester synthesis. Grignard coupling of the C6-unit (Z)-19 yields the C2o-diol 24, which has the carbon skeleton of vitamin A (22). The four conjugated double bonds in the side chain are formed by selective acetylation, partial hydrogenation to give 25 [19], and acid-catalysed elimination of water results in vitamin A acetate (26) (Scheme 4) [8]. 

The synthesis of 3 may be simplified further by linking the C20- units 59 or 60 oxidatively or reductively, respectively. Thus reduction of 60 with low-valency titanium compounds [64] or oxidation of 59 with triphenylphosphite-ozone adduct [65] afford 3 in yields of 85% and 75%, respectively. In a process developed at BASF the phosphonium salt 59 is reacted with hydrogen peroxide in aqueous alkaline solution [62]. After separation of triphenylphosphine oxide and thermal isomerization, (all- )-3 conforming to type specifications is obtained in yields of approximately 70% based on vitamin A acetate (26) (Scheme 17). 

Analogue of the C14-aldehyde synthesis for the preparation of Vitamin A acetate according to Hoffmann-la-Roche. 

Following are the final steps in one industrial synthesis of vitamin A acetate. 

Vitamin A acetate is an important nutrient additive and its synthesis is now carried out on a technical scale. The three major routes of preparation used today were developed by HofFmann-La Roche, Rhone Poulenc, and BASF [43]. For the work presented here, we were particularly concerned with the Wittig-Horner reaction between a C15 and a C5 precursor as it occurs in the BASF process [44,45]. This study describes the investigation of important process parameters for a synthesis that involves a thermally unstable ylide intermediate. In the current experiments, this intermediate is generated in situ and immediately converted in order to simulate the conditions in the technical process. However, while in a conventional process the reaction hardly can be performed under isothermal conditions due to the exothermic heat of reaction of about 250kJ/mol, the microreactor setup offers the opportunity to study relevant process parameters such as temperature, concentrations of starting materials, and mixing protocol of the components. 

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). 

Hoffmaim-La Roche has produced -carotene since the 1950s and has rehed on core knowledge of vitamin A chemistry for the synthesis of this target. In this approach, a five-carbon homologation of vitamin A aldehyde (19) is accompHshed by successive acetalizations and enol ether condensations to prepare the aldehyde (46). Metal acetyUde coupling with two molecules of aldehyde (46) completes constmction of the C q carbon framework. Selective reduction of the internal triple bond of (47) is followed by dehydration and thermal isomerization to yield -carotene (21) (Fig. 10). 

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