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

HRID 1773940ノート

反応式

HRID 1773940 の反応式
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+].C([O:72][C:73](=[O:86])[CH2:74][C:75]1[CH:80]=[CH:79][C:78]([O:81][CH:82]2[CH2:84][CH2:83]2)=[C:77](Cl)[CH:76]=1)(C)(C)C>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:76]=[C:75]([CH2:74][C:73]([OH:86])=[O:72])[CH:80]=[CH:79][C:78]=3[O:81][CH:82]3[CH2:84][CH2:83]3)[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

参加物

8

反応物 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 89649373Tert-butyl 2-(3-chloro-4-cyclopropoxyphenyl)acetate

生成物 1

HCID 896488918-(5-Carboxymethyl-2-cyclopropoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester

試薬・触媒・溶媒 3

HCID 167845palladium(II) acetate触媒HCID 962Water溶媒HCID 1140Toluene溶媒2 回

反応条件

温度
100 °C

実験手順

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 (82.3 mg, 0.2 mmol, 1.00 eq.) and potassium phosphate (84.9 mg, 0.4 mmol, 2.00 eq.) in toluene (0.6 mL) and water (35 μL) was stirred at r.t. during 2 min. A solution of (3-chloro-4-cyclopropoxy-phenyl)-acetic acid tert-butyl ester (57 mg, 0.2 mmol, 1.00 eq.) in toluene (0.6 mL) was added and the mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t., filtered through celite, and concentrated in vacuo. The residue, redissolved in MeCN (1.8 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. Trifluoroacetic acid (0.23 mL) was slowly added to an ice-cooled solution of the previous tert-butyl ester in DCM (0.23 mL). The reaction mixture was stirred at r.t. for 1.5 hours. The mixture was concentrated in vacuo without heating and the residue was redissolved in DMF (1.3 mL). Formic acid (0.2 mL) was added. The crude mixture 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 white foam.

後処理

  1. temperatureto cool to r.t.
  2. filtrationfiltered through celite
  3. concentrationconcentrated in vacuo
  4. dissolutionThe residue, redissolved in MeCN (1.8 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
  7. additionTrifluoroacetic acid (0.23 mL) was slowly added to an ice-
  8. temperaturecooled solution of the previous tert-butyl ester in DCM (0.23 mL)
  9. stirringThe reaction mixture was stirred at r.t. for 1.5 hours
  10. concentrationThe mixture was concentrated in vacuo
  11. temperaturewithout heating
  12. dissolutionthe residue was redissolved in DMF (1.3 mL)
  13. additionFormic acid (0.2 mL) was added
  14. customThe crude mixture was purified by prep
  15. customHPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated

出典と根拠

ORDレコード
ord-d913bd8b7b8545b08c1f69adece69f91
出典データセット
uspto-grants-2016_02
特許番号
US09255090B2

反応ノート

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