General description

Atropic acid has various physiological effects. For example: atropic acid shows antioxidant and anti-tumor effects. It can also be used as a local anesthetic, bactericide, and hemostatic agent. Besides, atropic acid has anti-inflammatory and anti thrombotic effects, as well as anti-aging and regulating human immune function. Atropic acid has been synthesized for the first time (in 9 steps and 17% overall yield from commercially available atropic acid) using the conjugate addition of lithium dibenzyl-amide to an N-α-phenylacryloyl SuperQuat derivative with in situ diastereoselective enolate protonation as the key step[1].

Synthesis

Fig. 1 The synthesis route of atropic acid

Carry out the carbonylation reactions in 50 mL stainless steel high-pressure reactors fitted with PTFE inserts. Heat the reactors using oil baths. Stir the reaction mixture with the aid of magnetic stirrer bars. Dissolve the calculated amounts of Pd catalyst, ligand, co-promoter, and substrate in the solvent of interest as detailed in the tables. Introduce the solution to the reactor vessel. Flush the reactor three times with carbon monoxide. Seal the reactor vessel. Pressurize the reactor vessel to 35 bar or as otherwise indicated. Heat the mixture to the required temperature for the specified period of time. After cooling to room temperature, depressurize the reactor. Distill the product from the catalyst under vacuum (150 °C, 0.01 mm Hg). Analyze the product using 1H and 13C NMR spectroscopy and GC-fID analysis. After completion of the reaction, remove the methanol solvent under vacuum. Add DCM (30 mL) to the residue. Wash the solution with water (3 x 10 mL). Dry the organic phase over magnesium sulfate. Remove the solvent under vacuum. Dissolve the residue in methanol. The synthesis route is shown in Fig. 1[2].

Fig. 2 The synthesis route of atropic acid

Add Pd(PPh3)2Cl2 (5 mol %), [BMIM]-PF6 (2.0 g), β-bromostyrene (2 mmol), water (0.18 mL, 10 mmol), and Et3N (0.57 mL, 4 mmol) into a 45-mL autoclave containing a glass liner and a magnetic stirring bar. Flush the autoclave three times with CO. Pressurize the autoclave to 20 bar of CO. Heat the mixture at 100 °C for 10 hours. Extract the resulting solution with water (3 mL x 4). Acidify the aqueous phase with aqueous hydrochloric acid (0.25 M). Extract the aqueous phase with diethyl ether (20 mL x 3). Combine the ether phases. Dry the ether phases over anhydrous MgSO4. Filter the ether phases through Celite. Concentrate the filtrate under reduced pressure. Wash the ionic liquid phase with 3 mL of diethyl ether. Add fresh starting material to the mixture to perform a second run reaction under the same conditions. Allow the reaction time for runs 2-5 to be 10, 10, 16 and 24 hours. After three runs, add 0.5 g of fresh ionic liquid to the mixture. The synthesis route is shown in Fig. 2.

Fig. 3 The synthesis route of atropic acid

Add an aqueous solution of 1 N sodium hydroxide (10 mL) to ethyl acrylate (5 mmol). Reflux the reaction mixture for 1 hour. After cooling down to room temperature, extract the resulting mixture with diethyl ether several times (2 x 20 mL). Acidify the aqueous layer with 3 N aqueous HCl solutions (pH < 1.0 by litmus paper test). Extract the aqueous layer with ethyl ether (3 x 20 mL). Dry the combined organic extracts over sodium sulfate. Filter the combined organic extracts. Concentrate the combined organic extracts. The synthesis route is shown in Fig. 3.

Applications

Atropic acid is an important chemical product widely used in medicine, spices, daily cosmetics, organic solvents, and as an intermediate in organic synthesis. Many atmospheric acid compounds have been synthesized and have attracted the attention of many scholars due to their broad application prospects in fields such as medicine, pesticides, dyes, chemical reagents, electronics, and aerospace[3].

References

[1]Long M T, B.A. Bartholomew, Smith M J, et al. Enzymology of oxidation of tropic acid to phenylacetic acid in metabolism of atropine by Pseudomonas sp. strain AT3.[J]. Journal of Bacteriology, 1997, 179(4):1044.DOI:10.1128/jb.179.4.1044-1050.1997.

[2]Han, Xiaoyu; et al. Enantioselective Cycloaddition of Allenes to Acrylates Catalyzed by Dipeptide-Derived Phosphines: Facile Creation of Functionalized Cyclopentenes Containing Quaternary Stereogenic Centers. Journal of the American Chemical Society (2011), 133(6), 1726-1729.

[3] Gross, Georg G., et al. "Chemical Synthesis of α-Formylphenylacetic Acid, the Postulated Precursor of Tropic Acid." Zeitschrift Für Naturforschung C 36.7-8(1981):611-614.