Synthesis and Characterization of Hydroxyl-Pinacolone Retinoate

All-trans retinoic acid (10) was synthesized by β-ionone (5) through knoevenagel condensation, reduction and hydrolysis reaction. Then, hydroxylpinacolone retinoate (11) was prepared by the esterification with 1-hydroxy3, 3-dimethylbutan-2-ketone. This route not only reduces the synthesis steps but also helps to increase the yield. The structure of the product was characterized by 1H NMR and 13C NMR.


Introduction
Vitamin A also known as retinol, vitamin A in a broad sense also includes retinol derivatives( Figure 1) such as retinene (1) retinoic acid (2) retinyl acetate (3) and retinyl palmitate (4) [1][2][3][4]. The structures are interconvertible [5,6]They have a wide range of physiological functions [7], including in vision [8] ,immune function [9]and tumor suppression [10]. vitamin A or vitamin A derivatives have been explored extensively. The long electron-rich conjugated polyene chains of the vitamin A molecule are highly unstable, it can be easily destroyed [11,14]. To avoid inactivation, vitamin A is often converted into vitamin A derivatives. It has been found that vitamin A ester derivatives have all the physiological functions of vitamin A, with higher stability and a wider range of applications [15][16][17][18]. Hydroxyl-pinacolone retinoate (12), one of the important derivatives of retinoic acid, could regulate the metabolism of the stratum corneum, which has been widely used in cosmetics fields, so the searches for efficient synthetic routes to these compounds are becoming increasingly important. The main synthetic routes for retinoic acid are C14+C6 represented by Roche [19] and C15+C5 represented by BAST [20] . In addition, the synthesis of retinoic acid was made by transition metal-catalyzed cross-coupling [21]. However, the method has major drawbacks. For example, the residue of transition metals is difficult to be separated. We have attempted to design a route with simple steps and mild conditions by adopting the knoevenagel condensation method.

Chemical synthesis
The C15+C6-C1 route was applied to the syntheses of alltrans retinoic acid. Starting from commercial β-ionone(5), the synthesis of C15 nitrile was made by the condensation with cyanoacetic acid and further decarboxylation, and the reduction of C15 nitrile to C15 aldehyde with DIBAL-H in tolueneinto. A knoevenagel condensation of C15 aldehydes with 3-methyl-2-butenoate in methanol led to retinoic acid methyl ester (8). Hydrolysis under alkaline conditions gave retinoic acid (9). Subsequent chlorination with PCl3 and finally esterification with 1-hydroxy-3, 3dimethylbutan -2-ketone provided hydroxyl-pinacolone retinoate (12).   As can be seen from Table 1, the yield gradually increased as the dosage of PCl 3 increased, and when n(retinoic acid):n(PCl 3 ) = 1:0.7, the product quality was 20.5g, yield 92%, and the dosage continued to increase with a slight decrease in yield. Therefore, the optimum amount of PCl 3 is n(retinoic acid):n(PCl 3 ) = 1:0.7. As can be seen from Table 2, the yield gradually increased with the increase of triethylamine dosage, when n(retinyl chloride): n(triethylamine) = 1:1.2, the product quality was 19.8g, yield 82.8%. Therefore, the optimum amount of triethylamine is n(retinyl chloride):n(Et 3 N) = 1:1.2. As can be seen from Table 3, the yield gradually increased with the extension of the titration time, and the product quality was 19.5g with a yield of 82.8% at a titration time of 30min, and the yield decreased slightly with further extension. Therefore, the optimum titration time is 30 min. As can be seen from Table 4, the reaction yield increases with the increase of reaction time, when the reaction time is 4h the yield is the largest, 82.8% continue to increase the reaction time yield increase is not obvious, because with the increase of time by-products increase, the yield decreases. Therefore, the optimum reaction time is 4h. As can be seen from Table 5, with the increase of temperature, the yield gradually increased, and the product quality was 19.8g with a yield of 82.85% at a temperature of 30°C. The yield decreased slightly when the reaction temperature continued to increase. Because the reaction temperature is too high to produce more byproducts, so the yield is reduced, therefore, the best reaction temperature is 30 ℃.

General
All chemicals are purchased from commercial sources and do not require further purification. (

Synthesis of all-trans retinoic acid methyl ester (8)
A slurry of n-BuOK (

Synthesis of 1-hydroxy-3,3-dimethylbutan-2ketone (11)
To the flask was added a 1-chloro-3,3-dimethylbutan-2one(2.7g 20 mmol), 72 g of water, stirred well and then warmed up to 50°C in a water bath. 45.2 g of aqueous sodium hydroxide solution with a mass fraction of 20% was added dropwise and the reaction was held for 6 hours after the dropwise addition, and the end point was detected by gas chromatography. The organic phase was extracted with ethyl acetate three times, the solvent was evaporated under reduced pressure, and the organic phase was combined and washed with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to obtain compound 11(1.95g,84%). 1 Figure 4.

Conclusion
The intermediate retinoic acid was synthesised through a series of reactions using β-ionone as the starting material and further synthesised as hydroxyl-pinacolone retinoate.
In the process of synthesizing retinoic acid, methyl 3methyl-2-butenoate was used as C6 module to reduce the synthesis steps and helps to increase the yield.