Pyridine → (6S,9aS)-N-Benzyl-8-((6-(3-((2S)-2,4-dimethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide

HRID 707519Notes

Reaction equation

HRID 707519 reaction equation
[CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33](F)[N:32]=3)[C:19](=[O:29])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:15]2[C:14](=[O:38])[CH2:13][N:12]1[CH2:39][CH:40]=[CH2:41])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH:48]1[CH2:51][CH:50]([N:52]2[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][C@@H:53]2[CH3:59])[CH2:49]1.C(C1C=CC=CC=1)C1C=CC=CC=1>CCCCCCC.C(OCC)C.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([N:48]4[CH2:51][CH:50]([N:52]5[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][C@@H:53]5[CH3:59])[CH2:49]4)[N:32]=3)[C:19](=[O:29])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:15]2[C:14](=[O:38])[CH2:13][N:12]1[CH2:39][CH:40]=[CH2:41])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

8

Reactant 4

HCID 1049PyridineHCID 7580DiphenylmethaneHCID 118162437(6S,9aS)-N-benzyl-8-((6-fluoropyridin-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamideHCID 118162468(2S)-1-(azetidin-3-yl)-2,4-dimethylpiperazine

Product 1

HCID 118162394(6S,9aS)-N-Benzyl-8-((6-(3-((2S)-2,4-dimethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamideYield 74%

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 8857Ethyl AcetateSolventHCID 8900HeptaneSolvent

Procedure

To a mixed solution of (6S,9aS)-N-benzyl-8-((6-fluoropyridin-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide (3.68 g, 6.59 mmol) described in Production Example 2-4 and pyridine (20 mL) was added a mixture (4.45 g) of (2S)-1-(azetidin-3-yl)-2,4-dimethylpiperazine and benzylbenzene described in Production Example 6-3 at room temperature. The resultant mixture was stirred under reflux for 5 hours and 45 minutes. The reaction mixture was cooled to room temperature, and was then concentrated under a reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1 and subsequently methanol) and then further purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) to give a solid material. Ethyl acetate, diethyl ether and heptane were added to the solid material, and a precipitate was collected by filtration to give the title compound (3.44 g, yield: 74%).

Workup

  1. customdescribed in Production Example 6-3 at room temperature
  2. temperatureunder reflux for 5 hours and 45 minutes
  3. concentrationwas then concentrated under a reduced pressure
  4. customThe resultant residue was purified by silica gel column chromatography (ethyl acetate
  5. custommethanol=20:1 and subsequently methanol) and then further purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1)
  6. customto give a solid material
  7. filtrationa precipitate was collected by filtration

Sources & evidence

ORD record
ord-8975acb97eda4320a7fcc3fff20b41e2
Source dataset
uspto-grants-2015_11
Patent number
US09174998B2

Reaction notes

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