反应详情

温度

80 °C

A solution of 4-((3S,4S)-3-fluoropiperidin-4-yl)phenol (7.10 g, 36.4 mmol, intermediate F) and DIEA (16 mL, 92 mmol) in 100 mL of acetonitrile was heated to 80° C. This solution was treated dropwise with a solution of (S)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl methanesulfonate (10.5 g, 37.0 mmol, intermediate J) in acetonitrile (80 mL) over a period of 4 hours. After the addition was completed, the reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was then allowed to cool to rt, and the volume was reduced by rotary evaporation to 80 mL. A satd. NH4Cl solution (100 mL) was then added, and the layers were separated. The aqueous layer was extracted with DCM (2×100 mL) and the organic layers were combined, dried over Na2SO4 and concentrated in vacuo to give a crude product. The crude product was purified by silica gel chromatography (750 g of silica gel) eluting with a gradient of 0% to 20% of solvent B in solvent A, where Solvent B=20% methanol/DCM and solvent A=DCM. Fractions containing the product were combined. Evaporation of the solvents gave 9.3 grams of the desired product with 97% purity by LC/MS analysis (conditions B). The product thus obtained (8.5 g) was slurried in acetone:hexane (1:5, 200 mL) and the solid product was isolated by filtration and air dried. Careful SFC analysis showed the presence of a 2.1% impurity in the product. Using a Cell4 0.46×25 cm 5 μm column and eluting with 45% methanol in CO2 at 3 mL/min, the desired product eluted at 3.800 minutes and the undesired impurity eluted at 4.848 minutes. The product was then further purified by SFC Chromatography using a Cell4 3×25 cm 5 μm column at 150 mL/min injecting 1.5 mL of a 80 mg/mL solution. Concentration of the active fractions provided 7.82 grams (20.4 mmol, 56%) of >99.7% pure example 1 as a white powder. LC/MS (Conditions B), RT=2.512 min, (M+H)+=383.3. 19F NMR δ −182.83. 1H NMR (400 MHz, chloroform-d) δ 7.20-7.08 (m, 6H), 6.98-6.78 (m, 2H), 5.68 (s, 1H), 4.77-4.54 (m, 1H), 4.53-4.34 (m, 2H), 3.68 (t, J=8.8 Hz, 1H), 3.41-3.29 (m, 1H), 3.28-3.09 (m, 2H), 2.82 (d, J=10.8 Hz, 1H), 2.74-2.54 (m, 2H), 2.47 (td, J=9.9, 3.6 Hz, 1H), 2.34 (s, 3H), 2.19-1.94 (m, 2H), 1.92-1.80 (m, 2H). 13C NMR (101 MHz, chloroform-d) δ 172.4, 154.9, 137.5, 133.3, 133.0, 129.5, 128.7, 128.3, 115.5, 92.6, 90.8, 65.0, 54.4, 54.2, 48.7, 48.0, 47.8, 46.8, 43.7, 31.7, 31.6, 21.1, 19.6.

1. additionAfter the addition
2. temperatureto cool to rt
3. customthe volume was reduced by rotary evaporation to 80 mL
4. additionNH4Cl solution (100 mL) was then added
5. customthe layers were separated
6. extractionThe aqueous layer was extracted with DCM (2×100 mL)
7. dry with materialdried over Na2SO4
8. concentrationconcentrated in vacuo
9. customto give a crude product
10. customThe crude product was purified by silica gel chromatography (750 g of silica gel)
11. washeluting with a gradient of 0% to 20% of solvent B in solvent A, where Solvent B=20% methanol/DCM and solvent A=DCM
12. additionFractions containing the product
13. customEvaporation of the solvents