Morpholine → (3R,4S)-4-(4-bromo-2-hydroxyphenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one

HRID 2252428Notes

Reaction equation

HRID 2252428 reaction equation
C([O:4][C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[C@H:12]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14](=[O:22])[C@@H:13]1[CH2:23][CH2:24][C@H:25]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)C=C.N1CCOCC1>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:11][C:9]1[CH:8]=[CH:7][C:6]([C@H:12]2[N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14](=[O:22])[C@@H:13]2[CH2:23][CH2:24][C@H:25]([O:33][Si:34]([C:37]([CH3:39])([CH3:38])[CH3:40])([CH3:36])[CH3:35])[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[C:5]([OH:4])[CH:10]=1

Participants

5

Reactant 2

HCID 8083MorpholineHCID 69124594HCID 69124594, compound

Product 1

HCID 59643934(3R,4S)-4-(4-bromo-2-hydroxyphenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-oneYield 83%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent

Procedure

(3R,4S)-4-[2-(Allyloxy)-4-bromophenyl]-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (1.34 g, 2.15 mmol) was dissolved in deoxygenated tetrahydrofuran (20 mL). Morpholine (1.8 mL, 1.8 g, 20.6 mmol) was added with additional deoxygenated tetrahydrofuran (5 mL). The reaction was purged with nitrogen and tetrakis(triphenylphosphine)palladium(0) (220 mg, 0.19 mmol) was added. The reaction was purged with nitrogen again. After 1.5 h at room temperature the reaction was diluted with ethyl acetate, washed twice with 1 N hydrochloric acid, saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate and filtered. The solution was treated with activated charcoal, filtered, concentrated and purified by chromatography (40 g silica gel, 6% to 80% ethyl acetate-hexane) to afford (3R,4S)-4-(4-bromo-2-hydroxyphenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (1.04 g, 83% yield); Rf 0.38 (1:4 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.28-7.18 (m, 6H), 7.09-6.92 (m, 6H), 5.91 (s, 1H), 4.93 (d, J=2.3 Hz, 1H), 4.65 (t, J=5.4 Hz, 1H), 3.06 (ddd, J=4.8, 2.3, 2.3 Hz, 1H), 1.98-1.77 (m, 4H), 0.86 (s, 9H), 0.006 (s, 3H), −0.16 (s, 3H) ppm; MS [M−H]+581.7.

Workup

  1. customwith additional deoxygenated tetrahydrofuran (5 mL)
  2. additionwas added
  3. customThe reaction was purged with nitrogen again
  4. additionAfter 1.5 h at room temperature the reaction was diluted with ethyl acetate
  5. washwashed twice with 1 N hydrochloric acid, saturated sodium bicarbonate solution, water and brine
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. additionThe solution was treated with activated charcoal
  9. filtrationfiltered
  10. concentrationconcentrated
  11. custompurified by chromatography (40 g silica gel, 6% to 80% ethyl acetate-hexane)

Sources & evidence

ORD record
ord-e62454e9e6414b4e9c76e19ee4b81b97
Source dataset
uspto-grants-2008_01
Patent number
US07320972B2

Reaction notes

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