Potassium Phosphate, Tribasic → acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{8-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-quinolin-6-yl}-benzyl ester

HRID 402962Notes

Reaction equation

[C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[N:30]=[CH:29][C:28]2[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=2)[C:22]1=[O:36])(=[O:3])[CH3:2].Cl[C:38]1[CH:39]=[C:40]2[C:45](=[C:46]([NH:48][C:49]3[N:54]=[CH:53][C:52]([C:55]([N:57]4[CH2:62][CH2:61][O:60][CH2:59][CH2:58]4)=[O:56])=[CH:51][CH:50]=3)[CH:47]=1)[N:44]=[CH:43][CH:42]=[CH:41]2.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O.C(O)CCC>[C:31]([C:26]1[CH:27]=[C:28]2[C:23](=[C:24]([F:35])[CH:25]=1)[C:22](=[O:36])[N:21]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:38]3[CH:39]=[C:40]4[C:45](=[C:46]([NH:48][C:49]5[CH:50]=[CH:51][C:52]([C:55]([N:57]6[CH2:58][CH2:59][O:60][CH2:61][CH2:62]6)=[O:56])=[CH:53][N:54]=5)[CH:47]=3)[N:44]=[CH:43][CH:42]=[CH:41]4)[C:6]=1[CH2:5][O:4][C:1](=[O:3])[CH3:2])[N:30]=[CH:29]2)([CH3:33])([CH3:32])[CH3:34].[C:31]([C:26]1[CH:27]=[C:28]2[C:23](=[C:24]([F:35])[CH:25]=1)[C:22](=[O:36])[N:21]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:38]3[CH:39]=[C:40]4[C:45](=[C:46]([NH:48][C:49]5[CH:50]=[CH:51][C:52]([C:55]([N:57]6[CH2:58][CH2:59][O:60][CH2:61][CH2:62]6)=[O:56])=[CH:53][N:54]=5)[CH:47]=3)[N:44]=[CH:43][CH:42]=[CH:41]4)[C:6]=1[CH2:5][OH:4])[N:30]=[CH:29]2)([CH3:34])([CH3:33])[CH3:32]

Participants

Conditions

Temperature: 110 °C

Procedure

In a 25 ml round bottom flask containing 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (563 mg, 683 μmol, Eq: 1.4), (6-(6-chloroquinolin-8-ylamino)pyridin-3-yl)(morpholino)methanone (180 mg, 488 μmol, Eq: 1.00), X-PHOS (34.9 mg, 73.2 μmol) and potassium phosphate (228 mg, 1.07 mmol) was added BuOH (7 mL) and H2O (1.65 mL). The flask was evacuated and backfilled with argon before addition of Pd(dba)2 (19.6 mg, 34.2 μmol). The flask was evacuated and backfilled with argon again and heated at 110° C. for 2.5 hrs. LC/MS showed the presence of desired product as a mixture with 6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{8-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-quinolin-6-yl}-phenyl)-2H-phthalazin-1-one. The reaction mixture was cooled to ambient temperature, diluted with 35 ml water and 35 ml EtOAc and shaken. The EtOAc phase was collected and washed with an equal volume of brine. The aqueous phase was back-extracted with 2×30 ml EtOAc. The combined organic extract was dried (MgSO4), and concentrated in vacuo. The crude product was purified by preparative thin layer chromatography (3 plates), eluting with 2% methanol/methylene chloride to provide the desired product (together with some 6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{8-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-quinolin-6-yl}-phenyl)-2H-phthalazin-1-one) as a light brown foamy solid (310 mg).

Workup

customThe flask was evacuated
customThe flask was evacuated
temperatureThe reaction mixture was cooled to ambient temperature
additiondiluted with 35 ml water and 35 ml EtOAc
customThe EtOAc phase was collected
washwashed with an equal volume of brine
extractionThe aqueous phase was back-extracted with 2×30 ml EtOAc
extractionThe combined organic extract
dry with materialwas dried (MgSO4)
concentrationconcentrated in vacuo
customThe crude product was purified by preparative thin layer chromatography (3 plates)
washeluting with 2% methanol/methylene chloride

Sources & evidence

ORD record: ord-8f0edb2c4fb7404e952b96bc47ad8e75
Source dataset: uspto-grants-2014_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08742098B2

Reaction notes

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