Acetone → HCID 15378772, compound

To a slurry of crude (R)-(4-phenylphenoxy)methyl-3-(2-phenylethyl)-3-[(4-phenylphenoxy)methoxy]hexanoate (X, EXAMPLE 7, 56.5 wt %, 49.32 g, 46.38 mmol) in toluene (500 ml) is added a solution of diisobutylaluminum hydride in toluene (1.52 M, 85 ml, 129.2 mmol, 2.79 equiv) while maintaining −20°. The mixture is slowly warmed to 1° over 2.5 hrs, then stirred ½ hr. Acetone (8.0 ml, 108.5 mmol, 2.34 equiv) is added and the mixture cannulated into an 18° solution of citric acid monohydrate (136 g, 647.2 mmol, 14.0 equiv) in water (433 ml) with controlled exotherm to 28°, rinsing with toluene (100 ml). The mixture is stirred at 20-25° for 1.5 hrs and the insolubles removed by vacuum filtration, washing with toluene. The phases are separated in the filtrate and the aqueous phase is washed with toluene (2×300 ml). The organic phases are dried over magnesium sulfate, then washed with aqueous sodium hydroxide (0.5 M, 2×500 ml). The organic phases are concentrated to 137 g net weight and methanol (250 ml) is added. The resultant slurry is is concentrated and methanol (250 ml) is added. The mixture is again concentrated and methanol (250 ml) added. The slurry is cooled to −60° and the insolubles removed by filtration. The filtrate is concentrated 60 g net weight, hexane (500 ml) is added, and the mixture concentrated to 22 g net weight. Hexane (500 ml) is added and the mixture again concentrated to 40 g net weight. Methylene chloride (25 ml) is added followed by a slow addition of hexane (500 ml) and pentane (250 ml) with cooling to −55°. The product is collected by vacuum filtration, washed with pentane (200 ml) and dried in a nitrogen stream to give the desired product. An analytical sample is obtained by chromatography (ethyl acetate/hexane) followed by crystallization (methylene chloride/hexane) to give the title compound, mp=49-53°; TLC Rf=0.14 (15% ethyl acetate/hexane); HPLC rt=9.18 min; NMR (CDCl3) 7.56-7.07, 5.36, 3.76-3.74, 2.63-2.58, 1.94-1.88, 1.70-1.65, 1.38-1.30, 0.93 δ; CMR (CDCl3) 157.05, 142.25, 140.73, 134.68, 128.70, 128.42, 128.29, 128.21, 126.76, 125.85, 116.07, 87.05, 81.85, 58.89, 38.77, 38.60, 38.23, 29.90, 17.04, 14.62 δ; MS (CI, NH3) m/z (relative intensity) 423 (2.3), 422 (9.9), 252 (100); [α]25D=6 (C=1.0, methylene chloride).

1. temperaturewhile maintaining −20°
2. temperatureThe mixture is slowly warmed to 1° over 2.5 hrs
3. customcannulated into an 18°
4. customto 28°
5. washrinsing with toluene (100 ml)
6. stirringThe mixture is stirred at 20-25° for 1.5 hrs
7. customthe insolubles removed by vacuum filtration
8. washwashing with toluene
9. customThe phases are separated in the filtrate
10. washthe aqueous phase is washed with toluene (2×300 ml)
11. dry with materialThe organic phases are dried over magnesium sulfate
12. washwashed with aqueous sodium hydroxide (0.5 M, 2×500 ml)
13. concentrationThe organic phases are concentrated to 137 g net weight and methanol (250 ml)
14. additionis added
15. concentrationThe resultant slurry is is concentrated
16. additionmethanol (250 ml) is added
17. concentrationThe mixture is again concentrated
18. additionmethanol (250 ml) added
19. temperatureThe slurry is cooled to −60°
20. customthe insolubles removed by filtration
21. concentrationThe filtrate is concentrated 60 g net weight, hexane (500 ml)
22. additionis added
23. concentrationthe mixture concentrated to 22 g net weight
24. additionHexane (500 ml) is added
25. concentrationthe mixture again concentrated to 40 g net weight
26. additionMethylene chloride (25 ml) is added
27. additionfollowed by a slow addition of hexane (500 ml) and pentane (250 ml)
28. temperaturewith cooling to −55°
29. filtrationThe product is collected by vacuum filtration
30. washwashed with pentane (200 ml)
31. customdried in a nitrogen stream

ORD record

ord-abc871b7a2ad40ed8ac7860b40472b66

Source dataset

uspto-grants-2001_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06265604B1