Potassium Phosphate, Tribasic → 8-(4-ethoxycarbonylmethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester

HRID 1773994Notes

Reaction equation

HRID 1773994 reaction equation
C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[CH2:30]([O:37][C:38]([N:40]1[CH2:49][CH2:48][C:47]2[C:42](=[C:43](B3OC(C)(C)C(C)(C)O3)[CH:44]=[CH:45][C:46]=2[F:50])[CH2:41]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:68]([O:70][C:71](=[O:82])[CH2:72][C:73]1[CH:78]=[CH:77][C:76](Br)=[C:75]([O:80][CH3:81])[CH:74]=1)[CH3:69]>C1(C)C=CC=CC=1.O.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:30]([O:37][C:38]([N:40]1[CH2:49][CH2:48][C:47]2[C:42](=[C:43]([C:76]3[CH:77]=[CH:78][C:73]([CH2:72][C:71]([O:70][CH2:68][CH3:69])=[O:82])=[CH:74][C:75]=3[O:80][CH3:81])[CH:44]=[CH:45][C:46]=2[F:50])[CH2:41]1)=[O:39])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1

Participants

9

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 896488855-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl esterHCID 89649140Ethyl 2-(4-bromo-3-methoxyphenyl)acetate

Product 1

HCID 896482498-(4-ethoxycarbonylmethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 3283Diethyl EtherSolvent

Conditions

Temperature
100 °C

Procedure

A mixture under N2 of palladium(II)acetate (13 mg, 0.06 mmol, 0.02 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (48 mg, 0.12 mmol, 0.04 eq.), 5-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (1.20 g, 2.92 mmol, 1.00 eq.) and potassium phosphate (1.24 g, 5.84 mmol, 2.00 eq.) in toluene (8 mL) and water (0.8 mL) was stirred at r.t. during 2 min. (4-Bromo-3-methoxy-phenyl)-acetic acid ethyl ester (797 mg, 2.92 mmol, 1.00 eq) was added and the mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t., diluted with Et2O (10 mL), filtered through celite, washed with Et2O and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane to Heptane+50% AcOEt) to yield 8-(4-ethoxycarbonylmethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester as a colorless oil.

Workup

  1. additionwas added
  2. temperatureto cool to r.t.
  3. filtrationfiltered through celite
  4. washwashed with Et2O
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane to Heptane+50% AcOEt)

Sources & evidence

ORD record
ord-080c3f2e7d9649d3816ff4006e04237d
Source dataset
uspto-grants-2016_02
Patent number
US09255090B2

Reaction notes

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