반응 #88184

반응 방정식

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

수율 92.6%

용매

THF

반응 조건

후처리

1. 1
   온도maintaining the temperature below 14° C.
2. 2
   세척rinse of the addition funnel
3. 3
   농축The mixture was concentrated
4. 4
   기타to remove THF
5. 5
   온도was cooled to 8° C
6. 6
   workup.ADDITIONHydrochloric acid (1N, 80 mL) was added dropwise
7. 7
   기타to form
8. 8
   workup.DISSOLUTIONto dissolve the solids
9. 9
   기타the layers were separated
10. 10
    추출the aqueous phase was further extracted with ethyl acetate (2 times with 100 mL)
11. 11
    세척The combined organics were washed with brine (4 times with 100 mL)
12. 12
    건조dried over sodium sulfate
13. 13
    여과filtered
14. 14
    농축concentrated under reduced pressure
15. 15
    온도heated to 75° C.
16. 16
    기타resulting in a yellow solution
17. 17
    기타forming a precipitate
18. 18
    온도the mixture was heated to 90° C.
19. 19
    workup.DISSOLUTIONto dissolve the solids
20. 20
    온도The solution was then cooled to 30° C.
21. 21
    workup.WAITwas held at that temperature for 16 hours
22. 22
    온도The mixture was further cooled to −1.5° C. for 3 hours
23. 23
    여과The resulting crystals were collected by filtration
24. 24
    세척rinsed with water (50 mL)
25. 25
    기타dried

실험 절차

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).

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