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Diphenylmethane → (6S,9aS)-N-Benzyl-8-((6-(3-(4-ethylpiperazin-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 707503
Notes
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Reaction equation

HRID 707503 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.CN1C(=O)CCC1.[NH:49]1[CH2:52][CH:51]([N:53]2[CH2:58][CH2:57][N:56]([CH2:59][CH3:60])[CH2:55][CH2:54]2)[CH2:50]1.C(C1C=CC=CC=1)C1C=CC=CC=1>O>[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:49]4[CH2:52][CH:51]([N:53]5[CH2:58][CH2:57][N:56]([CH2:59][CH3:60])[CH2:55][CH2:54]5)[CH2:50]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
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 7580DiphenylmethaneHCID 13387N-methyl-2-pyrrolidoneHCID 627863071-(Azetidin-3-yl)-4-ethylpiperazineHCID 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-carboxamide

Product 1

HCID 118162444
(6S,9aS)-N-Benzyl-8-((6-(3-(4-ethylpiperazin-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
Yield 37%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

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 (30.0 mg, 0.0537 mmol) described in Production Example 2-4 and NMP (2.0 mL) was added a mixture (45.0 mg) of 1-(azetidin-3-yl)-4-ethylpiperazine and benzylbenzene described in Production Example 1-3-2 at room temperature. The resultant mixture was irradiated with a microwave at 140° C. for 8 hours. Water was added to the reaction mixture, the resultant solution was extracted with ethyl acetate, and an organic layer was washed with saturated brine. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, the resultant residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1), and was then further purified by NH silica gel thin-layer chromatography (ethyl acetate). The resultant product was further purified by silica gel thin-layer chromatography (methanol) and was then filtrated using a NH silica gel to give the title compound (14.0 mg, yield: 37%).

Workup

  1. customdescribed in Production Example 1-3-2 at room temperature
  2. extractionthe resultant solution was extracted with ethyl acetate
  3. washan organic layer was washed with saturated brine
  4. dry with materialAn organic layer was dried over anhydrous magnesium sulfate
  5. filtrationfiltrated
  6. customThe solvent was evaporated under a reduced pressure
  7. customthe resultant residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1)
  8. customwas then further purified by NH silica gel thin-layer chromatography (ethyl acetate)
  9. customThe resultant product was further purified by silica gel thin-layer chromatography (methanol)
  10. filtrationwas then filtrated

Sources & evidence

ORD record
ord-1de0a6c383544731b772114cdb223f99
Source dataset
uspto-grants-2015_11
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09174998B2

Reaction notes

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