Reaction #88184

Reaction equation

Ethyl acetate

(R)-methyl 3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoate

lithium hydroxide

Water

water

→

(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoic acid

Yield 92.6%

Solvents

THF

Conditions

Workup

1. 1
   Temperaturemaintaining the temperature below 14° C.
2. 2
   Washrinse of the addition funnel
3. 3
   ConcentrationThe mixture was concentrated
4. 4
   Otherto remove THF
5. 5
   Temperaturewas cooled to 8° C
6. 6
   workup.ADDITIONHydrochloric acid (1N, 80 mL) was added dropwise
7. 7
   Otherto form
8. 8
   workup.DISSOLUTIONto dissolve the solids
9. 9
   Otherthe layers were separated
10. 10
    Extractionthe aqueous phase was further extracted with ethyl acetate (2 times with 100 mL)
11. 11
    WashThe combined organics were washed with brine (4 times with 100 mL)
12. 12
    Dryingdried over sodium sulfate
13. 13
    Filtrationfiltered
14. 14
    Concentrationconcentrated under reduced pressure
15. 15
    Temperatureheated to 75° C.
16. 16
    Otherresulting in a yellow solution
17. 17
    Otherforming a precipitate
18. 18
    Temperaturethe mixture was heated to 90° C.
19. 19
    workup.DISSOLUTIONto dissolve the solids
20. 20
    TemperatureThe solution was then cooled to 30° C.
21. 21
    workup.WAITwas held at that temperature for 16 hours
22. 22
    TemperatureThe mixture was further cooled to −1.5° C. for 3 hours
23. 23
    FiltrationThe resulting crystals were collected by filtration
24. 24
    Washrinsed with water (50 mL)
25. 25
    Otherdried

Procedure

A solution of (R)-methyl 3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoate (21.3 g, 43.5 mmol) in THF (100 mL) was cooled to 5° C. Aqueous 1.9M lithium hydroxide solution (50 mL, 96 mmol) was added via addition funnel, maintaining the temperature below 14° C., followed by a 30-mL water rinse of the addition funnel. The reaction mixture was warmed to 20-25° C. and was stirred at that temperature for 72 hours. The mixture was concentrated to remove THF, and then was cooled to 8° C. Hydrochloric acid (1N, 80 mL) was added dropwise, and a precipitate began to form. Ethyl acetate (200 mL) was added to dissolve the solids, and the layers were separated, and the aqueous phase was further extracted with ethyl acetate (2 times with 100 mL). The combined organics were washed with brine (4 times with 100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude solid (20.4 g) was slurried in ethanol (250 mL) and heated to 75° C., resulting in a yellow solution. Water (250 mL) was added slowly, forming a precipitate, and the mixture was heated to 90° C. to dissolve the solids. The solution was then cooled to 30° C. and was held at that temperature for 16 hours. The mixture was further cooled to −1.5° C. for 3 hours. The resulting crystals were collected by filtration, rinsed with water (50 mL), and then dried to afford (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoic acid (19.2 g). 1H NMR (500 MHz, CD3OD) δ 8.73 (s, 2H), 8.03 (s, 1H), 7.94 (d, 1H), 7.59 (d, 1H), 7.45 (t, 1H), 7.01 (dd, 1H), 6.92 (m, 2H), 6.86 (m, 1H), 4.60 (s, 2H), 4.37 (m, 1H), 4.14 (dd, 1H), 4.06 (dd, 1H), 3.92 (m, 4H), 2.07 (m, 1H), 1.97 (m, 2H), 1.58 (m, 1H), 1.29 (t, 3H). Chiral SFC: Chiralcel OJ-H, 4.6 mm×25 cm, 70:30 CO2:methanol, 0.2% isopropylamine, 2.5 mL/min, 210/254 nM; retention time (R)-enantiomer (Example 1) 4.13 min, (S)-enantiomer 2.35 min. MS (ES+) 477.3 (M+H).

Source