1,1'-Carbonyldiimidazole → Propane-2-sulfonic acid {17-[2-(3-fluoro-phenyl)-7-methoxy-8-methyl-quinazolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl}-amide

HRID 1443508Notes

Reaction equation

[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([O:18][CH:19]3[CH2:36][CH:35]4[CH:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38]([OH:40])=O)([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:45])[C:12]([O:43][CH3:44])=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C[NH:59][S:60]([CH:63]1[CH2:65][CH2:64]1)(=[O:62])=[O:61].C1CCN2C(=NCCC2)CC1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([O:18][CH:19]3[CH2:36][CH:35]4[CH:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38]([NH:59][S:60]([CH:63]([CH3:65])[CH3:64])(=[O:62])=[O:61])=[O:40])([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:45])[C:12]([O:43][CH3:44])=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1

Participants

Conditions

Temperature: 50 °C

Procedure

A mixture of the acid 159 (71 mg, 0.115 mmol) and CDI (37 mg, 0.228 mmol) in dry THF (10 mL) was heated at reflux for 2 h under N2. The reaction mixture was cooled 50° C. and a pre-mixed solution of methyl-cyclopropyl sulfonamide (43 mg, 0.349 mmol) and DBU (49 μL, 0.322 mmol) in 2 ml of dry THF was added to the reaction mixture. The reaction was stirred at 50° C. for 18 h. The solvent was evaporated and the residue was dissolved in CHCl3 and washed with citric acid (10% aq). The organic phase was dried with Na2SO4, filtered and the solvent was removed by rotary evaporation. The crude product was purified by HPLC on an Ace-5 C8 column (100×21.2 mm) with a gradient going from 35 to 60% acetonitrile (0.1% TFA) in H2O (0.1% TFA) over 8 minutes. The product was obtained as a white solid (30 mg, 36%), LRMS (M+H) 722.

Workup

temperaturewas heated
temperatureat reflux for 2 h under N2
customThe solvent was evaporated
dissolutionthe residue was dissolved in CHCl3
washwashed with citric acid (10% aq)
dry with materialThe organic phase was dried with Na2SO4
filtrationfiltered
customthe solvent was removed by rotary evaporation
customThe crude product was purified by HPLC on an Ace-5 C8 column (100×21.2 mm) with a gradient
waitgoing from 35 to 60% acetonitrile (0.1% TFA) in H2O (0.1% TFA) over 8 minutes

Sources & evidence

ORD record: ord-b721572a004147db85408454db2289fe
Source dataset: uspto-grants-2010_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07659245B2

Reaction notes

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