Potassium Phosphate, Tribasic → Tert-butyl 5-(2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-1,5-naphthyridin-3-yl)-3,6-dihydropyridine-1 (2H)-carboxylate

HRID 872063Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 872063
Br[C:2]1[C:3]([O:12][CH2:13][C@H:14]2[CH2:16][C@@H:15]2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][N:18]=2)=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2.CC1(C)C(C)(C)OB([C:33]2[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36][CH2:35][CH:34]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1COCC1.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C@H:15]2[CH2:16][C@@H:14]2[CH2:13][O:12][C:3]2[C:2]([C:35]3[CH2:36][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:33][CH:34]=3)=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][N:9]=3)[N:4]=2)=[N:18][CH:19]=1

Komponenten

9

Edukt 4

HCID 62657Potassium Phosphate, TribasicHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 49835909Tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylateHCID 1176891283-bromo-2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]-methoxy}-1,5-naphthyridine

Produkt 1

HCID 71062764Tert-butyl 5-(2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-1,5-naphthyridin-3-yl)-3,6-dihydropyridine-1 (2H)-carboxylate

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 167845palladium(II) acetateKatalysatorHCID 962WaterLösungsmittelHCID 8028TetrahydrofuranLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

A mixture of 3-bromo-2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]-methoxy}-1,5-naphthyridine (LL2) (50 mg, 0.13 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (52 mg, 0.17 mmol), tripotassium phosphate (55 mg, 0.26 mmol), S-Phos (5.3 mg, 0.01 mmol), and Pd(OAc)2 (1.5 mg, 0.006 mmol) in THF (0.6 mL) and water (0.1 mL) was heated at 100° C. for 14 hours. The reaction mixture was allowed to cool to room temperature. The mixture was then diluted with EtOAc (5 mL), washed with sodium bicarbonate (1 mL) and brine (1 mL), dried over MgSO4, filtered and concentrated. The resulting residue was purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-60% acetonitrile in water with 0.1% TFA modifier) to afford the title compound. 1H NMR (500 MHz, DMSO): δ 8.79 (dd, J=4.3, 1.6 Hz, 1 H), 8.18-8.06 (m, 3 H), 7.66 (dd, J=8.4, 4.2 Hz, 1 H), 7.24 (s, 2 H), 6.26 (s, 1 H), 4.54 (m, 1 H), 4.44 (m, 1 H), 4.26 (brs, 2 H), 3.77 (s, 3 H), 3.49-3.40 (m, 2 H), 2.27 (s, 2 H), 2.24-2.19 (m, 1 H), 1.80 (s, 1 H), 1.41 (s, 9 H), 1.23-1.15 (m, 2 H), 1.08 (dt, J=8.7, 4.6 Hz, 1 H); HRMS m/z (M+H) 489.2486 found, 489.2496 required.

Aufarbeitung

  1. temperatureto cool to room temperature
  2. washwashed with sodium bicarbonate (1 mL) and brine (1 mL)
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe resulting residue was purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-60% acetonitrile in water with 0.1% TFA modifier)

Quellen und Nachweise

ORD-Eintrag
ord-1664dbe00a05400ead197307f6476974
Quelldatensatz
uspto-grants-2015_03
Patentnummer
US08975261B2

Notizen zur Reaktion

Wird geladen…