Potassium Hydroxide → HCID 58815876, compound

HRID 2245887Notes

Reaction equation

HRID 2245887 reaction equation
[CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@@H:11]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[C:12]2[CH:13]=[C:14]([CH:24]=[CH:25][CH:26]=2)[C:15]([N:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)=[O:16])[C@@H:6]([CH3:34])[CH2:5]1)[CH:2]=[CH2:3].Cl.[NH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].[OH-].[K+].C([BH3-])#N.[Na+]>C(O)C>[CH2:43]([O:42][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][NH:36][CH:20]1[CH2:19][CH2:18][N:17]([C:15](=[O:16])[C:14]2[CH:24]=[CH:25][CH:26]=[C:12]([C@@H:11]([N:7]3[CH2:8][C@@H:9]([CH3:10])[N:4]([CH2:1][CH:2]=[CH2:3])[CH2:5][C@@H:6]3[CH3:34])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=3)[CH:13]=2)[CH2:22][CH2:21]1)[CH3:44]

Participants

6

Reactant 4

HCID 14797Potassium HydroxideHCID 5003444Sodium cyanoborohydrideHCID 126496614-Aminobutyrate ethyl hydrochlorideHCID 58815870HCID 58815870, compound

Product 1

HCID 58815876HCID 58815876, compoundYield 54.4%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

Procedure

A 100 mL round bottom flask equipped with a magnetic stir bar was flushed with nitrogen and charged with 2.31 g (5 mmol, 1 eq) of 1-{3-[(R)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-hydroxyphenyl)-methyl]-benzoyl}-4-piperidinone (Example 136), 1.41 g (8.4 mmol, 1.68 eq) of ethyl 4-aminobutyrate hydrochloride, 0.47 g (8.4 mmol, 1.68 eq) of potassium hydroxide, and 10 mL of ethanol. The reaction was stirred vigorously at room temperature under nitrogen for 2.5 hours. A solution of 0.32 g (5 mmol, 1 eq) of sodium cyanoborohydride in 5 mL of ethanol was added and the reaction was stirred overnight. The reaction was quenched by careful addition of 1 mL of saturated aqueous NH4Cl solution and stirred vigorously for 30 minutes and concentrated in vacuo. The residue was partitioned between 50 mL dichloromethane and water, and the aqueous solution was adjusted to pH=8-9 using saturated sodium bicarbonate solution. The organic layer was separated and dried over sodium sulfate/magnesium sulfate and the solvent was removed in vacuo, leaving 2.81 g of crude product as a viscous, amber-colored oil. Chromatography of this material on a pre-packed 4×15 cm Biotage® silica gel cartridge eluting with dichloromethane/ethyl acetate with 2% ammonium hydroxide yielded 1.57 g (53%) of 4-(1-{3-[(R)-((2S,5R)-4-Allyl-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperidin-4-ylamino)-butyric acid ethyl ester as an off-white foam. Calculated for C34H48N4O4 0.1 CH2Cl2: %C, 69.98; H, 8.30; N, 9.57. Found: %C, 70.07; H, 8.39; N, 9.65. 1H NMR (300 MHz, CDCl3): {tilde over (□)}{tilde over (□)}1{tilde over (□)}1m, 1H), 7.38-7.23 (m, 3H), 7.11 (t, J=7.9 Hz, 1H), 6.68-6.56 (m, 1H), 6.65 (t, J=7.9 Hz, 2H), 5.93-5.80 (m, 1H), 5.21-5.14 (m, 3H), 4.52 (br s, 1H), 4.14 (q, J=7.2 Hz, 2H), 3.67 (m, 1H), 3.36 (br d, 1H), 2.98-2.78 (m, 4H), 2.73-2.55 (m, 5H), 2.46 (m, 1H), 2.37 (t, J=7.2 Hz, 2H), 2.12 (dd, J=1, 9.3 Hz, 1H), 1.92 (m, 1H), 1.79 (quint, J=7.1 Hz, 2H), 1.26 (t, J=7.1 Hz, 3H), 1.15 (br d, J=5.6 Hz, 3H), 0.98 (d, J=6.2 Hz, 3H).

Workup

  1. customA 100 mL round bottom flask equipped with a magnetic stir bar
  2. customwas flushed with nitrogen
  3. stirringthe reaction was stirred overnight
  4. customThe reaction was quenched by careful addition of 1 mL of saturated aqueous NH4Cl solution
  5. stirringstirred vigorously for 30 minutes
  6. concentrationconcentrated in vacuo
  7. customThe residue was partitioned between 50 mL dichloromethane and water
  8. customThe organic layer was separated
  9. dry with materialdried over sodium sulfate/magnesium sulfate
  10. customthe solvent was removed in vacuo
  11. customleaving 2.81 g of crude product as a viscous, amber-colored oil
  12. washChromatography of this material on a pre-packed 4×15 cm Biotage® silica gel cartridge eluting with dichloromethane/ethyl acetate with 2% ammonium hydroxide

Sources & evidence

ORD record
ord-e92dca3c485a4b02af7ab6a081e495f0
Source dataset
uspto-grants-2010_03
Patent number
US07683168B2

Reaction notes

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