Triethylamine → 4-(((6S,9aS)-1-(Benzylcarbamoyl)-8-((6-(3-(4-ethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)-3-fluorophenyl dihydrogen phosphate

HRID 707529Notes

Reaction equation

[P:1](Cl)(Cl)(Cl)=[O:2].[CH2:6]([NH:13][C:14]([N:16]1[C@H:21]2[CH2:22][N:23]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([N:43]4[CH2:46][CH:45]([N:47]5[CH2:52][CH2:51][N:50]([CH2:53][CH3:54])[CH2:49][CH2:48]5)[CH2:44]4)[N:38]=3)[C:24](=[O:35])[C@H:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]=3[F:34])[N:20]2[C:19](=[O:55])[CH2:18][N:17]1[CH2:56][CH:57]=[CH2:58])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[OH-:66].[Na+].C(OCC)(=[O:70])C>O.C1COCC1>[P:1]([OH:2])([OH:70])([O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C@@H:25]2[N:20]3[C@@H:21]([N:16]([C:14](=[O:15])[NH:13][CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:17]([CH2:56][CH:57]=[CH2:58])[CH2:18][C:19]3=[O:55])[CH2:22][N:23]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([N:43]4[CH2:46][CH:45]([N:47]5[CH2:52][CH2:51][N:50]([CH2:53][CH3:54])[CH2:49][CH2:48]5)[CH2:44]4)[N:38]=3)[C:24]2=[O:35])=[C:28]([F:34])[CH:29]=1)=[O:66]

Participants

Conditions

Temperature: -15 °C

Procedure

To a mixed solution of phosphorus oxychloride (257 μL, 2.76 mmol) and THF (10.0 mL) was dropwisely added a mixed solution of (6S,9aS)-N-benzyl-8-((6-(3-(4-ethylpiperazin-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 (1.00 g, 1.38 mmol) described in Example 1, triethylamine (768 μL, 5.52 mmol) and THF (10.0 mL) over 10 minutes under a nitrogen atmosphere at −15° C. or lower. The reaction mixture was stirred at −15° C. or lower for 1 hour and 10 minutes. To the reaction mixture was dropwisely added a mixed solution of a 5 N aqueous sodium hydroxide solution (2.03 mL, 10.1 mmol) and water (21.0 mL) over 5 minutes at 10° C. or lower. The reaction mixture was stirred at room temperature for 35 minutes, then ethyl acetate was added to the reaction mixture, and then the resultant solution was partitioned. An aqueous layer was further washed with ethyl acetate, and then 5 N hydrochloric acid was added to the solution to adjust the pH value of the solution at a neutral value. The solvent was distilled away from the reaction mixture under a reduced pressure. Dichloromethane, ethanol and methanol were added to the resultant residue and then stirred, and then the resultant suspension was filtrated using Celite. The solvent was distilled away from the filtrate under a reduced pressure, and the resultant residue was purified by ODS silica gel column chromatography (elution solvent: water/methanol) to give the title compound (881 mg, yield: 79%).

Workup

stirringThe reaction mixture was stirred at room temperature for 35 minutes
customthe resultant solution was partitioned
washAn aqueous layer was further washed with ethyl acetate
addition5 N hydrochloric acid was added to the solution
distillationThe solvent was distilled away from the reaction mixture under a reduced pressure
additionDichloromethane, ethanol and methanol were added to the resultant residue
stirringstirred
filtrationthe resultant suspension was filtrated
distillationThe solvent was distilled away from the filtrate under a reduced pressure
customthe resultant residue was purified by ODS silica gel column chromatography (elution solvent: water/methanol)

Sources & evidence

ORD record: ord-0c4efebff6dd4b1ea527a11b0812fb7d
Source dataset: uspto-grants-2015_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09174998B2

Reaction notes

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