Potassium Phosphate, Tribasic → (+/-)-5-Fluoro-8-[2-methoxy-4-(1-methoxycarbonyl-ethoxy)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester

HRID 1773990Notes

Reaction equation

HRID 1773990 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+].[CH3:68][O:69][C:70](=[O:83])[CH:71]([O:73][C:74]1[CH:79]=[CH:78][C:77](Br)=[C:76]([O:81][CH3:82])[CH:75]=1)[CH3:72]>C1(C)C=CC=CC=1.O.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:77]3[CH:78]=[CH:79][C:74]([O:73][CH:71]([C:70]([O:69][CH3:68])=[O:83])[CH3:72])=[CH:75][C:76]=3[O:81][CH3:82])[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

Participants

8

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 89649485Methyl 2-(4-bromo-3-methoxyphenoxy)propanoate

Product 1

HCID 118353171(+/-)-5-Fluoro-8-[2-methoxy-4-(1-methoxycarbonyl-ethoxy)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 1140TolueneSolvent2×

Conditions

Temperature
100 °C

Procedure

A mixture under N2 of palladium (II) acetate (0.4 mg, 2 μmol, 0.01 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.7 mg, 4 μmol, 0.02 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 (95 mg, 0.20 mmol, 1.00 eq.) and potassium phosphate (85 mg, 0.40 mmol, 2.00 eq.) in toluene (0.6 mL) and water (0.035 mL) was stirred at r.t. for 2 min. A solution of (±)-2-(4-Bromo-3-methoxy-phenoxy)-propionic acid methyl ester (58 mg, 0.2 mmol, 1.00 eq.) in toluene (0.6 mL) was added and the mixture was stirred at 100° C. for 2 days. The mixture was allowed to cool to r.t., filtered through celite and concentrated in vacuo. The crude residue, redissolved in MeCN (1.5 mL) and formic acid (0.2 mL), was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the title compound as a colorless oil.

Workup

  1. temperatureto cool to r.t.
  2. filtrationfiltered through celite and
  3. concentrationconcentrated in vacuo
  4. dissolutionThe crude residue, redissolved in MeCN (1.5 mL)
  5. customformic acid (0.2 mL), was purified by prep
  6. customHPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated

Sources & evidence

ORD record
ord-088b3609641a4c21b9cb4036de0a68f3
Source dataset
uspto-grants-2016_02
Patent number
US09255090B2

Reaction notes

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