Sodium Bicarbonate → Ethyl 3-(5-amino-2-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)-benzo[f][1,7]naphthyridin-8-yl)propanoate

HRID 631174Notes

Reaction equation

HRID 631174 reaction equation
Cl[C:2]1[C:3]([C:21]#[N:22])=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[CH:12][C:11]=2[CH3:20])[CH:7]=1.C(OC([NH:30]C1C=C(CCC(OCC)=O)C=CC=1B1OC(C)(C)C(C)(C)O1)=O)(C)(C)C.C1(P(C2CCCCC2)C2C=CC=[CH:62][C:61]=2[C:66]2[C:71](OC)=[CH:70][CH:69]=[CH:68][C:67]=2OC)CCCCC1.[C:82](=[O:85])(O)[O-:83].[Na+].C(O)C[CH2:89][CH3:90].O>C(OCC)(=O)C.O.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:30][C:21]1[C:3]2[N:4]=[CH:5][C:6]([C:8]#[C:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[CH:12][C:11]=3[CH3:20])=[CH:7][C:2]=2[C:69]2[CH:70]=[CH:71][C:66]([CH2:61][CH2:62][C:82]([O:83][CH2:89][CH3:90])=[O:85])=[CH:67][C:68]=2[N:22]=1

Participants

9

Reactant 5

HCID 516892Sodium BicarbonateHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 22253497Water butanolHCID 670655293-Chloro-5-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)picolinonitrileHCID 67065550Ethyl 3-(3-(tert-butoxycarbonylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate

Product 1

HCID 67065523Ethyl 3-(5-amino-2-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)-benzo[f][1,7]naphthyridin-8-yl)propanoate

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

A solution of 3-chloro-5-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)picolinonitrile (10) (1.0 equiv.), ethyl 3-(3-(tert-butoxycarbonylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (5) (1.25 equiv.), tris(dibenzylideneacetone)dipalladium(0) (0.10 equiv.), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.20 equiv.), and sodium bicarbonate (3.0 equiv.) in n-butanol/H2O (5:1, 0.2M) was degassed and stirred at 100° C. overnight. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-40% ethyl acetate in DCM first to remove the impurity, then 0-4% MeOH in DCM to give ethyl 3-(5-amino-2-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)-benzo[f][1,7]naphthyridin-8-yl)propanoate (11). Further purification was accomplished by precipitating and washing in hot ether.

Workup

  1. temperatureAfter cooling to ambient temperature
  2. customThe two phases were separated
  3. extractionthe aqueous layer was extracted twice with ethyl acetate
  4. washThe combined organic layers were washed with brine
  5. dry with materialdried over anhydrous MgSO4
  6. concentrationconcentrated in vacuo
  7. customThe crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO)
  8. customto remove the impurity

Sources & evidence

ORD record
ord-5f3dcea1c0e04df28f31a6d535ad1474
Source dataset
uspto-grants-2016_04
Patent number
US09320748B2

Reaction notes

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