1,2-Dichloroethane → 4-[2-(4-hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-beta-carbolin-8-yl)-amide

HRID 552248Notes

Reaction equation

HRID 552248 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[N:23]([CH2:24][C:25]([OH:27])=O)[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[NH:30]1[CH2:35][CH2:34][CH:33]([CH2:36][OH:37])[CH2:32][CH2:31]1.C(Cl)CCl.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:19][O:20][C:21]([CH3:28])([CH3:29])[CH2:22][N:23]3[CH2:24][C:25]([N:30]3[CH2:35][CH2:34][CH:33]([CH2:36][OH:37])[CH2:32][CH2:31]3)=[O:27])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1

Participants

6

Reactant 4

HCID 111,2-DichloroethaneHCID 962WaterHCID 4207714-PiperidinemethanolHCID 59337527[5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid

Product 1

HCID 671657504-[2-(4-hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-beta-carbolin-8-yl)-amideYield 62%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

[5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid (200 mg, 0.48 mmol) and piperidin-4-yl-methanol (111 mg, 0.96 mmol) were dissolved in pyridine (4 mL). The resulting yellow solution was stirred at room temperature for 10 min and then EDC (184 mg, 0.96 mmol) was added in a single portion. The reaction mixture was allowed to stir over night (16 h). Water (4 mL) was added and the mixture was concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate (50 mL) and 1 M aqueous potassium carbonate. The aqueous layer was back-extracted with ethyl acetate (3×50 mL) and the combined extracts were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel chromatography (methylene chloride and methanol gradient) to afford pure 4-[2-(4-hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-beta-carbolin-8-yl)-amide as a yellow foam (152 mg, 62%). The bis-HCl salt was prepared by adding 2 equivalents of conc. HCl to an ethanolic solution of the freebase. Concentration, followed by ether trituration afforded the salt as a free-flowing, yellow powder. 1H-NMR (freebase, 300 MHz, CDCl3) δ: 11.03 (d, 1H), 10.51 (d, 1H), 8.97-8.80 (m, 1H), 8.47-8.27 (m, 2H), 7.94-7.76 (m, 2H), 4.84 (d, 1H), 4.16-3.77 (m, 3H), 3.68-3.26 (m, 5H), 3.08 (ddd, 1H), 2.89-2.64 (m, 2H), 2.50-2.37(m, 2H), 1.98-1.70 (m, 3H), 1.38 (s, 3H), 1.25 (s, 3H), 1.19-0.97 (m, 1). MS (NH4OAc standard conditions, ES+) e/z=514 (M+H)+DAD Rf=1.51 min

Workup

  1. stirringto stir over night (16 h)
  2. concentrationthe mixture was concentrated under reduced pressure
  3. customThe resulting residue was partitioned between ethyl acetate (50 mL) and 1 M aqueous potassium carbonate
  4. extractionThe aqueous layer was back-extracted with ethyl acetate (3×50 mL)
  5. washthe combined extracts were washed with water and brine
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude residue was purified by silica gel chromatography (methylene chloride and methanol gradient)

Sources & evidence

ORD record
ord-baa4342656bb4b8ca4496cc1bb9bcd44
Source dataset
uspto-grants-2011_05
Patent number
US07951801B2

Reaction notes

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