Methylamine → (2R)-2-{(3R,6R)-3-(2,3-Dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl}-2-(2,6-dimethyl-3-pyridinyl)-N-methylethanamide

HRID 402854Notes

Reaction equation

HRID 402854 reaction equation
[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[NH:15][C:14](=[O:16])[C@@H:13]([C@@H:17]([CH3:20])[CH2:18][CH3:19])[N:12]([CH:21]([C:32]2[C:33]([CH3:39])=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[C:22]([NH:24][C:25]2C=CC=CC=2O)=[O:23])[C:11]1=[O:40].C(N1C=CN=C1)(N1C=CN=C1)=O.CN.O1CCCC1>ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[NH:15][C:14](=[O:16])[C@@H:13]([C@@H:17]([CH3:20])[CH2:18][CH3:19])[N:12]([C@H:21]([C:32]2[C:33]([CH3:39])=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[C:22]([NH:24][CH3:25])=[O:23])[C:11]1=[O:40]

Participants

6

Reactant 4

HCID 6329MethylamineHCID 8028TetrahydrofuranHCID 682631,1'-CarbonyldiimidazoleHCID 569495922-{(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl}-2-(2,6-dimethyl-3-pyridinyl)-N-(2-hydroxyphenyl)acetamide2×

Product 1

HCID 11705315(2R)-2-{(3R,6R)-3-(2,3-Dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl}-2-(2,6-dimethyl-3-pyridinyl)-N-methylethanamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

2-{(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl}-2-(2,6-dimethyl-3-pyridinyl)-N-(2-hydroxyphenyl)acetamide (intermediate 2) (0.400 g, 0.74 mmol) and 1,1′-carbonyldiimidazole (0.192 g, 1.18 mmol) in dry dichloromethane (10 mL) were stirred at room temperature under N2 for 7 hrs. The mixture was treated with a 2M solution of methylamine in tetrahydrofuran (1.849 mL, 3.70 mmol) and left to stand overnight at room temperature. The solvents were blown down under N2 and the residue was purified on a Redisep silica column (35 g) eluted with 0-10% methanol in ethyl acetate followed by further purification on a Kromasil KR100-10-C18 reverse-phase column eluted with aqueous acetonitrile (20-45% MeCN) containing 0.1% formic acid. This gave the title compound as a white lyophilisate (30%) after freeze-drying from 1,4-dioxane.

Workup

  1. waitleft
  2. customthe residue was purified on a Redisep silica column (35 g)
  3. washeluted with 0-10% methanol in ethyl acetate
  4. customfollowed by further purification on a Kromasil KR100-10-C18 reverse-phase column
  5. washeluted with aqueous acetonitrile (20-45% MeCN)
  6. additioncontaining 0.1% formic acid

Sources & evidence

ORD record
ord-333d99d2bc3a48f49d0eb777da4b57e6
Source dataset
uspto-grants-2014_06
Patent number
US08742099B2

Reaction notes

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