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

HRID 1773940노트

반응식

HRID 1773940 반응식
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

참가 물질

8

반응물 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

생성물 1

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

시약·촉매·용매 3

HCID 167845palladium(II) acetate촉매HCID 962Water용매HCID 1140Toluene용매2회

반응 조건

온도
100 °C

실험 절차

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.

후처리

  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

출처 및 근거

ORD 기록
ord-d913bd8b7b8545b08c1f69adece69f91
출처 데이터셋
uspto-grants-2016_02
특허 번호
US09255090B2

반응 노트

불러오는 중…