(6S,9aS)-N-benzyl-6-((2-fluoro-4-hydroxyphenyl)methyl)-8-((6-fluoropyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide → (6S,9aS)-N-Benzyl-8-((6-(3-((3S)-3,4-dimethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((2-fluoro-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 707511Notes

Reaction equation

HRID 707511 reaction equation
[CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34](F)[N:33]=3)[C:19](=[O:30])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:29])[N:15]2[C:14](=[O:39])[CH2:13][N:12]1[CH2:40][CH:41]=[CH2:42])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:43]1[CH2:46][CH:45]([N:47]2[CH2:52][CH2:51][N:50]([CH3:53])[C@@H:49]([CH3:54])[CH2:48]2)[CH2:44]1>N1C=CC=CC=1>[CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([N:43]4[CH2:46][CH:45]([N:47]5[CH2:52][CH2:51][N:50]([CH3:53])[C@@H:49]([CH3:54])[CH2:48]5)[CH2:44]4)[N:33]=3)[C:19](=[O:30])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:29])[N:15]2[C:14](=[O:39])[CH2:13][N:12]1[CH2:40][CH:41]=[CH2:42])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

4

Reactant 2

HCID 118162423(6S,9aS)-N-benzyl-6-((2-fluoro-4-hydroxyphenyl)methyl)-8-((6-fluoropyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamideHCID 118162554(S)-4-(Azetidin-3-YL)-1,2-dimethylpiperazine

Product 1

HCID 118162446(6S,9aS)-N-Benzyl-8-((6-(3-((3S)-3,4-dimethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamideYield 58.2%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

To a mixed solution of (6S,9aS)-N-benzyl-6-((2-fluoro-4-hydroxyphenyl)methyl)-8-((6-fluoropyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide (4.00 g 6.94 mmol) described in Production Example 1-1-6 and pyridine (100 mL) was added (2S)-4-(azetidin-3-yl)-1,2-dimethylpiperazine (2.35 g, 13.9 mmol) described in Production Example 4-3 at room temperature. The resultant mixture was stirred under reflux for 6 hours and 50 minutes. The reaction mixture was cooled to room temperature, and then concentrated under a reduced pressure. The resultant residue was purified by silica gel column chromatography (methanol), and then purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) to give the title compound (2.93 g, yield: 58%).

Workup

  1. customdescribed in Production Example 4-3 at room temperature
  2. temperatureunder reflux for 6 hours and 50 minutes
  3. concentrationconcentrated under a reduced pressure
  4. customThe resultant residue was purified by silica gel column chromatography (methanol)
  5. custompurified by NH silica gel column chromatography (ethyl acetate:methanol=20:1)

Sources & evidence

ORD record
ord-63f65d20c19f44b680add1b30c635e1b
Source dataset
uspto-grants-2015_11
Patent number
US09174998B2

Reaction notes

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