Lithium Hydroxide → ((1S)-5-{3-[[5-(4-ethylphenyl)-2-pyrimidinyl](methyl)amino]propoxy}-2,3-dihydro-1h-inden-1-yl)acetic acid

HRID 603460Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 603460
Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:17][CH2:16]3)=[N:6][CH:7]=1.[CH2:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[CH3:29].[CH2:39](Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].[Li+].[OH-]>C1COCC1.O.CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1.C1(C)C=CC=CC=1>[CH2:28]([C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:3]=[N:4][C:5]([N:8]([CH3:39])[CH2:9][CH2:10][CH2:11][O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[C@H:18]([CH2:22][C:23]([OH:25])=[O:24])[CH2:17][CH2:16]4)=[N:6][CH:7]=2)=[CH:32][CH:31]=1)[CH3:29]

Komponenten

12

Edukt 5

HCID 3939Lithium HydroxideHCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 2734352Boronic acid, (4-ethylphenyl)-HCID 59300487ethyl ((1S)-5-{3-[(5-bromo-2-pyrimidinyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate

Produkt 1

HCID 59300470((1S)-5-{3-[[5-(4-ethylphenyl)-2-pyrimidinyl](methyl)amino]propoxy}-2,3-dihydro-1h-inden-1-yl)acetic acidAusbeute 729,4 %

Reagenzien, Katalysatoren, Lösungsmittel 6

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)KatalysatorHCID 702EthanolLösungsmittelHCID 962WaterLösungsmittelHCID 1140TolueneLösungsmittelHCID 8028TetrahydrofuranLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
75 °C

Versuchsvorschrift

To a round-bottom flask charged with ethyl ((1S)-5-{3-[(5-bromo-2-pyrimidinyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 282, 100 mg, 0.220 mmol), 4-ethylphenyl boronic acid (134 mg, 0.090 mmol) and PdCl2(dppf).CH2Cl2 (16.4 mg, 0.020 mmol) were added toluene (6 mL) and 1,4-dioxane (1.12 mL). A flow of argon was passed through the mixture for 30 min. Then a 2 N aqueous solution of Na2CO3 (1.12 mL, 2.24 mmol, 2 N aqueous solution) was added, and the reaction was heated to 75° C. for 18 h. The reaction mixture was cooled to rt. Filtration through a short plug of silica gel gave the crude ester, which was dissolved in a mixture of THF (3 mL), water (3 mL), and EtOH (1.5 mL). Subsequently, LiOH (57 mg, 2.39 mmol) was added, and the reaction was stirred at rt for 18 h. The reaction mixture was concentrated under reduced pressure, and then purified by preparative HPLC. The desired fractions were concentrated under reduced pressure. The residue was dissolved in CH2Cl2, and treated for 15 min with Dowex® 66 weakly basic resin. The mixture was then filtered and the filtrate concentrated under reduced pressure to give the product (65 mg, 61%). 1H NMR (400 MHz, CDCl3) δ 1.29 (t, 3H), 1.73-1.84 (m, 1H), 2.16 (qt, 2H), 2.33-2.51 (m, 2H), 2.70 (q, 2H), 2.77-2.96 (m, 3H), 3.24 (s, 3H), 3.49-3.56 (m, 1H), 3.87 (t, 2H), 4.03 (t, 2H), 6.72 (dd, 1H), 6.78 (d, 1H), 7.08 (d, 1H), 7.27 (d, 2H), 7.39 (d, 2H), 8.24 (s, 2H); LC-MS: RT=3.39 min, (M+H)+ 446.3.

Aufarbeitung

  1. temperatureThe reaction mixture was cooled to rt
  2. filtrationFiltration through a short plug of silica gel
  3. customgave the crude ester, which
  4. concentrationThe reaction mixture was concentrated under reduced pressure
  5. custompurified by preparative HPLC
  6. concentrationThe desired fractions were concentrated under reduced pressure
  7. dissolutionThe residue was dissolved in CH2Cl2
  8. additiontreated for 15 min with Dowex® 66 weakly basic resin
  9. filtrationThe mixture was then filtered
  10. concentrationthe filtrate concentrated under reduced pressure

Quellen und Nachweise

ORD-Eintrag
ord-d981fba93b32419486aa5cb03b79189b
Quelldatensatz
uspto-grants-2011_03
Patentnummer
US07906653B2

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