Methanol → (1R,2R)-2-(4-cyanophenyl)cyclopropane-1-carboxylic acid

Temperature

70 °C

A round bottom flask was charged with 21B (11.6 g, 47.7 mmol, 1 eq) and MeOH (55 mL). With moderate stirring, a solution was formed. To the solution was added a solution of NaOH (5.7 g, 143.1 mmol, 3 eqs) in H2O (30 mL). The resulting mixture was heated in an oil bath at a temperature of 70° C. for 4 h. The reaction mixture was analyzed for completion using 1H NMR. After confirming completion of the reaction, the reaction mixture was concentrated to one-third its volume and the rest of the reaction mixture was diluted by the addition of 50 mL of a NaOH (0.5 M) solution. The resulting mixture was washed with 2×25 mL of MTBE. The aq. layer was separated and acidified by the dropwise addition of conc. HCl until the pH of the mixture was ˜1. The acidified mixture was extracted with 2×50 mL of EtOAc. The combined organic extracts were dried over MgSO4 and evaporated to dryness on a rotary evaporator to give crude product. The crude product was purified by flash chromatography, eluting with 1-10% MeOH in DCM. The product was isolated as a single spot on TLC. However, 1H NMR analysis of this product indicated a small amount of impurities were present. This material was then dissolved in a 1 M solution of NaOH (30 mL) and washed with 2×25 mL of EtOAc. The aq. layer was separated and re-acidified to pH ˜1 by the dropwise addition of conc. HCl. The mixture formed was extracted with EtOAc (50 mL). The organic extract was evaporated to dryness to give 3.1 g 21C as a white solid (36.4% yield). Note: a very small amount of impurities were still present in the material, as revealed by 1H NMR. 1H NMR (400 MHz, CDCl3-d) δ ppm 1.37-1.46 (m, 1H) 1.47-1.55 (m, 1H) 1.87-1.96 (m, 1H) 2.43-2.49 (m, 1H) 7.38 (d, 2H) 7.74 (d, 2H) 12.43 (s, 1H).

1. customWith moderate stirring, a solution was formed
2. customcompletion of the reaction
3. concentrationthe reaction mixture was concentrated to one-third its volume
4. additionthe rest of the reaction mixture was diluted by the addition of 50 mL of a NaOH (0.5 M) solution
5. washThe resulting mixture was washed with 2×25 mL of MTBE
6. customThe aq. layer was separated
7. additionacidified by the dropwise addition of conc. HCl until the pH of the mixture
8. extractionThe acidified mixture was extracted with 2×50 mL of EtOAc
9. dry with materialThe combined organic extracts were dried over MgSO4
10. customevaporated to dryness on a rotary evaporator
11. customto give crude product
12. customThe crude product was purified by flash chromatography
13. washeluting with 1-10% MeOH in DCM
14. customThe product was isolated as a single spot on TLC
15. washwashed with 2×25 mL of EtOAc
16. customThe aq. layer was separated and re-acidified to pH ˜1 by the dropwise addition of conc. HCl
17. customThe mixture formed
18. extractionwas extracted with EtOAc (50 mL)
19. extractionThe organic extract
20. customwas evaporated to dryness

ORD record

ord-838d4c4423514c2a8344387f1ed2b6f5

Source dataset

uspto-grants-2015_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09029381B2