Toluene → N-(4-(2-(4-carbamoylphenyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 1676305Notes

Reaction equation

HRID 1676305 reaction equation
[C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[F:13][C:14]1[CH:15]=[C:16]([N:31]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[C:32]([C:34]2([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35]2)=[O:33])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[CH:27]=[C:28](I)[S:29][C:22]=12.C([O-])([O-])=O.[Cs+].[Cs+].C1(C)C=CC=CC=1>O.CCO>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:28]2[S:29][C:22]3[C:23](=[N:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]3[CH:18]=[CH:17][C:16]([N:31]([C:40]4[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=4)[C:32]([C:34]4([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35]4)=[O:33])=[CH:15][C:14]=3[F:13])[CH:27]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2]

Participants

7

Reactant 4

HCID 1140TolueneHCID 10796Cesium carbonateHCID 27378114-Aminocarbonylphenylboronic acidHCID 67347909N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Product 1

HCID 67347374N-(4-(2-(4-carbamoylphenyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 13%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

A sealable vial, was charged with 4-carbamoylphenylboronic acid (0.0312 g, 0.189 mmol), N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Example 12, Step A, 0.100 g, 0.0947 mmol), Cs2CO3 (0.0309 g, 0.0947 mmol), toluene (2 mL) and EtOH (1 mL). Under nitrogen Pd(PPh3)4 (0.00547 g, 0.00473 mmol) was added and the reaction heated to 80° C. for 18 hours. The mixture was then cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (30 mL) and MeOH (2 mL). The organics were dried over sodium sulfate, filtered and concentrated to get crude product. The crude product was purified by reverse phase C-18 column chromatography to get product (6.9 mg, 13%) as a white solid. LRMS (esi+) 585 m/z (M+1) detected. 1H NMR (d6-DMSO, 400 MHz) δ 8.48 (d, J=6 Hz, 1H), 7.96 (m, 5H), 7.87 (m, 1H), 7.57 (m, 2H), 7.37 (m, 2H), 7.07 (t, J=9.0 Hz, 2H), 6.65 (d, J=6 Hz, 1H), 1.64 (s, 4H).

Workup

  1. additionUnder nitrogen Pd(PPh3)4 (0.00547 g, 0.00473 mmol) was added
  2. temperatureThe mixture was then cooled to room temperature
  3. extractionextracted with ethyl acetate (30 mL) and MeOH (2 mL)
  4. dry with materialThe organics were dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto get crude product
  8. customThe crude product was purified by reverse phase C-18 column chromatography

Sources & evidence

ORD record
ord-711cb9e2670e4ac38c69a34e63ac1aa5
Source dataset
uspto-grants-2011_08
Patent number
US08003662B2

Reaction notes

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