Hydrochloric Acid → N-{[5-hydroxy-6-(1-methylethyl)-2-({3-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]phenyl}methyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine

HRID 2046297Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 2046297
Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][N:35]=2)[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:23][C:12]1[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10][N:9]([CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:37]3[CH:36]=[N:35][C:34]([N:31]4[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]4)=[CH:39][CH:38]=3)[CH:3]=2)[C:14](=[O:15])[C:13]=1[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17]

Komponenten

8

Edukt 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 27696181-Methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineHCID 54739211N-{[2-[(3-Bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine

Produkt 1

HCID 54739190N-{[5-hydroxy-6-(1-methylethyl)-2-({3-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]phenyl}methyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycineAusbeute 65,8 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 178418397HCID 178418397, VerbindungKatalysatorHCID 962WaterLösungsmittel2×HCID 312751,4-DioxaneLösungsmittel

Versuchsvorschrift

To a 5 mL microwave tube was added N-{[2-[(3-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 79, 31 mg, 0.073 mmol), 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (22.16 mg, 0.073 mmol), potassium carbonate (303 mg, 2.192 mmol), and tetrakis(triphenylphosphine)palladium (0) (2.53 mg, 2.192 μmol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (4 ml) and acidified with 1N HCl (1 ml) then filtered to remove any residue followed by purification by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA)) to afford the title compound N-{[5-hydroxy-6-(1 -methylethyl)-2-({3-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]phenyl}methyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (32 mg, 0.048 mmol, 65.7% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.88 (s, 1H), 12.98 (br. s., 1H), 10.18 (t, J=5.56 Hz, 1 H), 9.71 (br. s., 1H), 8.46 (d, J=2.27 Hz, 1H), 7.91 (dd, J=8.84, 2.53 Hz, 1H), 7.52-7.61 (m, 2H), 7.42 (t, J=8.08 Hz, 1H), 7.23 (d, J=7.58 Hz, 1H), 7.07 (d, J=9.09 Hz, 1H), 5.32 (s, 2H), 4.48 (d, J=12.63 Hz, 2H), 4.09 (d, J=5.56 Hz, 2H), 3.52 (d, J=10.36 Hz, 2H), 3.00-3.26 (m, 5H), 2.86 (d, J=4.04 Hz, 3H), 1.21 (d, J=6.82 Hz, 6H). MS (ES+) m/e 521 [M+H]+.

Aufarbeitung

  1. customThe mixture was irradiated at 100° C. for 20 minutes
  2. filtrationthen filtered
  3. customto remove any residue
  4. customfollowed by purification by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA))

Quellen und Nachweise

ORD-Eintrag
ord-6d64b234d6be4f9ea85193ee337839b4
Quelldatensatz
uspto-grants-2013_11
Patentnummer
USRE044613E1

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