Thioanisole → (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

HRID 707496Notes

Reaction equation

HRID 707496 reaction equation
[CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[N:40]=3)[C:19](=[O:37])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28]CC4C=CC=CC=4)=[CH:24][C:23]=3[F:36])[N:15]2[C:14](=[O:46])[CH2:13][N:12]1[CH2:47][CH:48]=[CH2:49])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(SC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[N:40]=3)[C:19](=[O:37])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:36])[N:15]2[C:14](=[O:46])[CH2:13][N:12]1[CH2:47][CH:48]=[CH2:49])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

4

Reactant 2

HCID 7520ThioanisoleHCID 118162441(6S,9aS)-N-Benzyl-6-((4-(benzyloxy)-2-fluorophenyl)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

Product 1

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-carboxamideYield 99.6%

Reagents, catalysts & solvents 1

HCID 6422Trifluoroacetic acidSolvent

Procedure

To a mixed solution of (6S,9aS)-N-benzyl-6-((4-(benzyloxy)-2-fluorophenyl)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 (5.04 g, 7.56 mmol) described in Production Example 1-1-5 and TFA (20 mL) was added thioanisole (3.55 mL, 30.2 mmol) at room temperature. The resultant mixture was stirred at room temperature for 13 hours and 50 minutes. The reaction mixture was concentrated under a reduced pressure, sodium hydrogen carbonate and water were added to the residue, and the resultant solution was extracted with ethyl acetate. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) to give the title compound (4.34 g, yield: quantitative).

Workup

  1. concentrationThe reaction mixture was concentrated under a reduced pressure, sodium hydrogen carbonate and water
  2. additionwere added to the residue
  3. extractionthe resultant solution was extracted with ethyl acetate
  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)

Sources & evidence

ORD record
ord-32bf7b7cf3564f90879bb65d6ca7672e
Source dataset
uspto-grants-2015_11
Patent number
US09174998B2

Reaction notes

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