Toluene → Ethyl 2-(4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylamino)nicotinate

HRID 1676410Notes

Reaction equation

HRID 1676410 reaction equation
Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].[NH2:19][C:20]1[CH:48]=[CH:47][C:23]([O:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]3[CH:31]=[C:32]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]4)[S:33][C:26]=23)=[C:22]([F:49])[CH:21]=1.C1(C)C=CC=CC=1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCO>[C:43]([O:42][C:40]([N:37]1[CH2:38][CH2:39][CH:34]([C:32]2[S:33][C:26]3[C:27](=[N:28][CH:29]=[CH:30][C:25]=3[O:24][C:23]3[CH:47]=[CH:48][C:20]([NH:19][C:2]4[N:12]=[CH:11][CH:10]=[CH:9][C:3]=4[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:21][C:22]=3[F:49])[CH:31]=2)[CH2:35][CH2:36]1)=[O:41])([CH3:46])([CH3:44])[CH3:45]

Participants

8

Reactant 4

HCID 1140TolueneHCID 10796Cesium carbonateHCID 2796614Ethyl chloronicotinateHCID 67346565Tert-butyl 4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)piperidine-1-carboxylate

Product 1

HCID 67345485Ethyl 2-(4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylamino)nicotinateYield 65.5%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 702EthanolSolventHCID 962WaterSolvent

Conditions

Temperature
110 °C

Procedure

A microwave vial was charged with ethyl 2-chloronicotinate (0.209 g, 1.13 mmol), Cs2CO3 (0.331 g, 1.01 mmol), tert-butyl 4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)piperidine-1-carboxylate (Example 154, Step A, 0.200 g, 0.451 mmol), Palladium acetate (0.0101 g, 0.0451 mmol), PdCl2(dppf)-dcm (0.0185 g, 0.0225 mmol), toluene (2 mL) and EtOH (1 mL). The mixture was heated to 110° C. for 3 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The organics were isolated and dried (MgSO4). After filtration and concentration, the crude product was purified by preparative TLC (2.0 mm thickness, eluting with EtOAc. The product (175 mg, 59%) was isolated as a yellow solid. LRMS (esi+)593 m/z (M+1) detected.

Workup

  1. temperatureAfter cooling to room temperature
  2. extractionextracted with EtOAc
  3. customThe organics were isolated
  4. dry with materialdried (MgSO4)
  5. filtrationAfter filtration and concentration
  6. customthe crude product was purified by preparative TLC (2.0 mm thickness
  7. washeluting with EtOAc

Sources & evidence

ORD record
ord-701cdff1304f4e59af3b69c89e3a7cc4
Source dataset
uspto-grants-2011_08
Patent number
US08003662B2

Reaction notes

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