Cyclobutanecarboxylic acid, 1-amino-, methyl ester, hydrochloride (9CI) Chemical Properties

storage temp. 

under inert gas (nitrogen or Argon) at 2-8°C

form 

solid

color 

White

Water Solubility 

Slightly soluble in water.

Sensitive 

Air Sensitive

Safety Information

HS Code 

2916200090

Cyclobutanecarboxylic acid, 1-amino-, methyl ester, hydrochloride (9CI) Usage And Synthesis

Uses

Used as a primary and secondary intermediate for pharmaceutical and organic synthesis.

Synthesis

Acetyl chloride (4.2 ml, 58.6 mmol) was added slowly and dropwise to a stirred solution of 1-aminocyclobutane-1-carboxylic acid (2.7 g, 23.4 mmol) in methanol (40 ml) at 0 °C. The reaction mixture was then warmed to room temperature and stirred continuously for about 12 hours. The reaction progress was monitored by thin layer chromatography (TLC). After completion of the reaction, the mixture was concentrated under reduced pressure to afford methyl 1-aminocyclobutane-1-carboxylate hydrochloride (3.02 g, yield: 100%) as a white solid. To a stirred solution of 1-aminocyclobutane-1-carboxylic acid hydrochloride (3.02 g, 23.4 mmol) in tetrahydrofuran (THF, 40 ml) at 0 °C was added triethylamine (N(Et)3, 9.6 ml, 69.6 mmol) and di-tert-butyl dicarbonate ((Boc)2O, 6.4 ml, 23.8 mmol). The reaction mixture was then warmed to room temperature and stirred continuously for about 12 hours. The reaction progress was monitored by TLC. Upon completion of the reaction, saturated ammonium chloride (NH4Cl) solution was added and extracted with ethyl acetate (EtOAc, 2 x 100 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate (Na2SO4) and concentrated under reduced pressure to give the crude product. Purification by fast column chromatography using ethyl acetate-hexane (3:7) as eluent gave the target product (5.32 g, yield: 100%) as an oil. 1H NMR (300 MHz, DMSO-d6): δ 7.64 (s, 1H), 3.60 (s, 3H), 2.44-2.38 (m, 2H), 2.14-2.04 (m, 2H), 1.88-1.80 (m, 2H), 1.36 (s, 9H).

References

[1] Patent: WO2017/17630, 2017, A1. Location in patent: Page/Page column 80-81
[2] Journal of the American Chemical Society, 1997, vol. 119, # 49, p. 11807 - 11816
[3] Patent: CN104230766, 2017, B. Location in patent: Paragraph 0382; 0383; 0384
[4] Patent: CN104341351, 2018, B. Location in patent: Paragraph 0356-0359
[5] Journal of Medicinal Chemistry, 1984, vol. 27, # 12, p. 1663 - 1668

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