Application and preparation of 1-phenyl-1-cyclopropanecarboxylic acid_Kain Industrial Additive

Background and overview^[1]

1-Phenyl-1-cyclopropanecarboxylic acid can be used as an intermediate for pharmaceutical and chemical synthesis. If 1-phenyl-1-cyclopropanecarboxylic acid is inhaled, please move the patient to fresh air; if there is skin contact, take off contaminated clothing, wash the skin thoroughly with soap and water, and seek medical treatment if you feel uncomfortable; If eye contact occurs, separate eyelids, rinse with running water or saline, and seek medical attention immediately; if ingested, rinse mouth immediately, do not induce vomiting, and seek medical attention immediately.

Apply^[1]

1-Phenyl-1-cyclopropanecarboxylic acid can be used as an intermediate for pharmaceutical and chemical synthesis, such as the synthesis of the following compounds:

The specific steps are: add 1-phenyl-1-cyclopropanecarboxylic acid (3g), triethylamine (5.15mL), molecular sieve 4A° (3g) and anhydrous dioxane (3g) into a 500mL round-bottom flask. 30mL). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 15 minutes. Then diphenylphosphoryl azide (6.1g) was slowly added, and the reaction mixture was stirred at 60°C for 1 hour and 80°C for 10 minutes. Then tert-butanol (15 mL) was added under nitrogen atmosphere. The reaction was stirred at 80°C for 2 hours. After cooling to room temperature, the reaction mixture was filtered through a bed of celite and washed with dioxane (3 × 20 mL). The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography using ethyl acetate/hexane (1.0:9.0) as the eluent to obtain (1-phenylcyclopropyl)carbamic acid tert-butyl ester ( 2.5g), as yellow oil. 1H-NMR (CDCl3): δ0.98-1.13 (m, 4H), 1.49 (s, 9H), 7.14-7.35 (m, 5H), 5.3 (s, 1H). MS: 234(M+H)+.

Preparation ^[1]

Step 1: Under nitrogen protection, add a stirring solution of sodium hydride (60%) (16.4g) in anhydrous DMSO (160mL) to THF (20mL) at 0℃ Benzyl cyanide (20g). The reaction mixture was stirred at 0℃ for 30 minutes, and then a solution of ethyl bromide (29g) in anhydrous THF (20mL) was added dropwise at 0℃ under nitrogen protection. . After stirring at room temperature for 2 h, the reaction was slowly quenched with saturated ammonium chloride solution (250 mL). The reaction mixture was diluted with ethyl acetate (500 mL), and the aqueous phase was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (250 mL) and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain crude 1-phenylcyclopropanecarbonitrile (20 g) as a yellow liquid, which was used as it was for further reactions. 1H-NMR (CDCl3): δ1.48-1.55 (m, 2H), 1.66-1.73 (m, 2H), 7.30-7.40 (m, 5H).

Step 2: Add aqueous potassium hydroxide solution (50%, 100mL) to a solution of 1-phenylcyclopropanecarbonitrile (20g) in ethanol (100mL) at room temperature. The reaction mixture was stirred at 100°C for 16 hours and then cooled to room temperature. The reaction mixture was concentrated to remove ethanol, and the aqueous layer was washed with dichloromethane (2 × 200 mL). Slowly neutralize the aqueous layer with concentrated HCl and adjust the pH to 3-4. The solid obtained was filtered, washed with water (3×50mL), and dried under vacuum to obtain �The required 1-phenyl-1-cyclopropanecarboxylic acid (12g) is a white solid. 1H-NMR (CDCl3): δ1.26-1.30 (m, 2H), 1.59-1.66 (m, 2H), 7.20-7.30 (m, 5H), 8.6 (s, 1H). MS: 163(M+H)+.

Main reference materials

[1] WO2014160689. PIPERAZINE AND HOMOPIPERAZINE DERIVATIVES AS HIV ATTACHMENT INHIBITORS