反応 #88184

反応方程式

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

収率 92.6%

溶媒

THF

反応条件

後処理

1. 1
   温度maintaining the temperature below 14° C.
2. 2
   洗浄rinse of the addition funnel
3. 3
   濃縮The mixture was concentrated
4. 4
   その他to remove THF
5. 5
   温度was cooled to 8° C
6. 6
   workup.ADDITIONHydrochloric acid (1N, 80 mL) was added dropwise
7. 7
   その他to form
8. 8
   workup.DISSOLUTIONto dissolve the solids
9. 9
   その他the layers were separated
10. 10
    抽出the aqueous phase was further extracted with ethyl acetate (2 times with 100 mL)
11. 11
    洗浄The combined organics were washed with brine (4 times with 100 mL)
12. 12
    乾燥dried over sodium sulfate
13. 13
    ろ過filtered
14. 14
    濃縮concentrated under reduced pressure
15. 15
    温度heated to 75° C.
16. 16
    その他resulting in a yellow solution
17. 17
    その他forming a precipitate
18. 18
    温度the mixture was heated to 90° C.
19. 19
    workup.DISSOLUTIONto dissolve the solids
20. 20
    温度The solution was then cooled to 30° C.
21. 21
    workup.WAITwas held at that temperature for 16 hours
22. 22
    温度The mixture was further cooled to −1.5° C. for 3 hours
23. 23
    ろ過The resulting crystals were collected by filtration
24. 24
    洗浄rinsed with water (50 mL)
25. 25
    その他dried

実験手順

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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