Synthesis
GENERAL STEPS: To a stirred mixed solution of nebivolol impurity 35 (2a-f) in tetrahydrofuran (THF, 2 mL) and methanol (MeOH, 1 mL) was added slowly and dropwise 0.25 M aqueous lithium hydroxide (LiOH) solution (1.05 equiv.) at room temperature with continuous stirring for 2 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure and subsequently acidified with dilute hydrochloric acid (HCl). The crude product was extracted with ethyl acetate (EtOAc), the organic phases were combined and dried over anhydrous magnesium sulfate (MgSO4). After filtration, the solvent was evaporated under reduced pressure to give the crude product. Further purification by n-hexane crystallization gave the target products 6a-f.
4.2.22 Synthesis of (R)-6-fluorochroman-2-carboxylic acid (6a): compound 6a (89 mg) was obtained in 96% yield by treating 2a (100 mg, 0.47 mmol) as raw material in the above general steps according to the method described in section 4.2.21.
1H NMR (δ, ppm): 6.88-6.80 (m, 2H), 6.75 (dd, 3J = 8.7, 4JH-F = 2.6, 1H), 4.74 (dd, 1H, J = 7.6, 3.5), 2.90-2.75 (m, 2H), 2.33 (m, 1H), 2.18 (m, 1H).
13C NMR (δ, ppm): 175.8, 157.2 (d, 1JC-F = 237.9), 148.9 (d, 4JC-F = 2.1), 122.3 (d, 3JC-F = 7.5), 117.8 (d, 3JC-F = 8.1), 115.4 (d, 2JC-F = 22.7), 114.5 (d, 2JC- F = 23.2), 73.2, 24.1, 23.5 (d, 4JC-F = 1.1).
Spin: [α]D20 = -12.6 (c 1.0, DMF) {literature value [α]D20 = -13.4 (c 1.0, DMF)}.
Enantiomeric excess (ee) > 99% was determined using a Chiralcel ODH column with n-hexane/2-propanol/trifluoroacetic acid = 90:10:0.5 as the mobile phase at a flow rate of 1.0 mL/min and retention times tR = 6.92 min (S) and 9.62 min (R).
High resolution mass spectrometry (HRMS) calculated value of C10H9FO3 [M]+: 196.0530, measured value: 196.0531.
References
[1] Tetrahedron Asymmetry, 2015, vol. 26, # 17, p. 912 - 917
[2] Patent: KR2017/37154, 2017, A. Location in patent: Paragraph 0291-0293
