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Citric Acid → Cyclopropanesulfonic acid {17-[2-(3-fluoro-phenyl)-7-methoxy-8-methyl-quinazolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4,6*]octadec-7-ene-4-carbonyl}-amide

HRID 1443507
Notes
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Reaction equation

HRID 1443507 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](O)=[O:39])([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.[CH:58]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.[Cl-].[Na+].O.CCOC(C)=O>[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:64][S:61]([CH:58]6[CH2:60][CH2:59]6)(=[O:63])=[O:62])=[O:39])([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
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

9

Reactant 5

HCID 311Citric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 15765418CyclopropanesulfonamideHCID 6841046617-[2-(3-Fluoro-phenyl)-7-methoxy-8-methyl-quinazolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4,6*]octadec-7-ene-4-carboxylic acid

Product 1

HCID 75290660
Cyclopropanesulfonic acid {17-[2-(3-fluoro-phenyl)-7-methoxy-8-methyl-quinazolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4,6*]octadec-7-ene-4-carbonyl}-amide

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
50 °C

Procedure

A mixture of the acid 159 (200 mg, 0.324 mmol) and CDI (105 mg, 0.649 mmol) in dry THF (12 mL) was heated at reflux for 2 h under N2. The reaction mixture was cooled 50° C. and a pre-mixed solution of cyclopropyl sulfonamide (118 mg, 0.973 mmol) and DBU (138 μL, 0.908 mmol) in 2 ml of dry THF was added to the reaction mixture. The reaction was stirred at 50° C. for 18 h. The solution was pored in a separatory funnel and acidified with approx. 20 mL citric acid 10% (aq). Additional brine (20 mL) and EtOAc (40 mL) was added. The mixture was extracted with EtOAc and washed with brine, thereafter 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 title compound was obtained as a white solid (144 mg, 62%), LRMS (M+H) 720.

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 2 h under N2
  3. customThe solution was pored in a separatory funnel
  4. extractionThe mixture was extracted with EtOAc
  5. washwashed with brine
  6. dry with materialdried with Na2SO4
  7. filtrationfiltered
  8. customthe solvent was removed by rotary evaporation
  9. customThe crude product was purified by HPLC on an Ace-5 C8 column (100×21.2 mm) with a gradient
  10. waitgoing from 35 to 60% acetonitrile (0.1% TFA) in H2O (0.1% TFA) over 8 minutes

Sources & evidence

ORD record
ord-e07ef61bca7c4ee5a1df93d2ee57648c
Source dataset
uspto-grants-2010_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07659245B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes