1-Hydroxy-1-cyclopropanecarboxylic acid

Synthesis

(1) Synthesis of Compound 2

Compound 1 (3.41 g, 29.6 mmol, 1.0 eq) was dissolved in 40 ml of sulfuric acid aqueous solution A (prepared by adding 1.62 mL of 98% concentrated sulfuric acid to water, with a sulfuric acid molar equivalent of 1.0 eq). The solution was cooled to 0-5 °C in an ice bath. 10 ml of sodium nitrite (2.25 g, 32.6 mmol, 1.1 eq) aqueous solution was added to the reaction solution and stirred at room temperature for 1 hour. Then, the above reaction solution was added dropwise to 100 ml of refluxed sulfuric acid aqueous solution B (prepared by adding 1.62 mL of 98% concentrated sulfuric acid to water, with a sulfuric acid molar equivalent of 1.0 eq). After the addition was complete, heating was stopped, and the mixture was cooled to room temperature. TLC analysis confirmed the reaction was complete. The mixture was then extracted three times with ethyl acetate (3 x 100 mL), and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to give compound 2 (2.57 g, 22.1 mmol), a colorless oily liquid, with a yield of 74.8%. The 1H-NMR spectra of compound 2 (400 Hz, DMSO) were: 0.951–0.959 (t, 2h), 1.112–1.121 (t, 2h), 3.624 (s, 3H), 6.177 (s, 1H). In the synthesis of compound 2, the sulfuric acid aqueous solution used cannot be replaced with hydrochloric acid or nitric acid solution, otherwise it will easily lead to cyclopropane ring-opening. The reaction solution of sulfuric acid aqueous solution A was added dropwise to sulfuric acid aqueous solution B to shorten the reaction time of the raw materials and products in the reaction system, allowing the raw materials to react rapidly after addition, as prolonged reaction time will lead to cyclopropane ring-opening. (2) Synthesis of Compound 3 Compound 2 (113.7 mg, 0.98 mmol, 1.0 eq) was dissolved in 7 mL of a mixture of tetrahydrofuran and water (5:2), and then lithium hydroxide (240 mg, 10.02 mmol, 10 eq) was added in portions. The reaction mixture was heated in an oil bath to 30 °C and reacted for 12 hours. After the reaction was complete, it was cooled to room temperature, and the pH of the reaction was adjusted to 5-6 with hydrochloric acid (2N) aqueous solution. The mixture was extracted three times with ethyl acetate (3*20 mL), and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the target compound 3 (84.7 mg, 0.83 mmol), a white solid, with a yield of 84.8%.

Chemical Properties

Beige fine crystalline powder

Uses

A hydroxycarboxylic acid as additive enhancing topical actions of therapeutic agents.

Synthesis Reference(s)

Tetrahedron Letters, 25, p. 1269, 1984 DOI: 10.1016/S0040-4039(01)80131-3