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

HRID 1822425Notes

Reaction equation

HRID 1822425 reaction equation
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.CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[CH:36]=2)O1.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:35]3[CH:40]=[CH:39][N:38]=[C:37]([N:41]4[CH2:42][CH2:43][NH:44][CH2:45][CH2:46]4)[CH:36]=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]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 162179482-(1-Piperaziny) pyridine-4-boronic acid pinacol esterHCID 54739211N-{[2-[(3-Bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine

Product 1

HCID 54739189N-{[5-hydroxy-6-(1-methylethyl)-3-oxo-2-({3-[2-(1-piperazinyl)-4-pyridinyl]phenyl}methyl)-2,3-dihydro-4-pyridazinyl]carbonyl}glycineYield 46.6%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

Procedure

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-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (21.13 mg, 0.073 mmol), potassium carbonate (30.3 mg, 0.219 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 (3 ml) and acidified with 1N HCl. The mixture was then filtered to remove residual salts and purified by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA)). The title compound, N-{[5-hydroxy-6-(1-methylethyl)-3-oxo-2-({3-[2-(1-piperazinyl)-4-pyridinyl]phenyl}methyl)-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (22 mg, 0.034 mmol, 46.2% yield), was obtained as a white solid tfa salt. 1H NMR (400 MHz, DMSO-d6) d ppm 15.88 (s, 1 H), 12.90 (br. s., 1H), 10.17 (t, J=5.81 Hz, 1H), 8.75 (br. s., 2H), 8.22 (d, J=5.56 Hz, 1H), 7.72 (s, 1H), 7.70 (d, J=8.59 Hz, 1H), 7.48 (t, J=7.71 Hz, 1H), 7.35 (d, J=7.58 Hz, 1H), 7.14 (s, 1H), 7.01 (dd, J=5.31, 1.01 Hz, 1H), 5.34 (s, 2H), 4.09 (d, J=5.56 Hz, 2H), 3.75-3.84 (m, 4H), 3.13-3.27 (m, 5H), 1.21 (d, J=6.82 Hz, 6H). MS (ES+) m/e 507 [M+H]+.

Workup

  1. customThe mixture was irradiated at 100° C. for 20 minutes
  2. filtrationThe mixture was then filtered
  3. customto remove residual salts
  4. custompurified by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA))

Sources & evidence

ORD record
ord-ee944041d16b4714881cc163c561fe2e
Source dataset
uspto-grants-2009_10
Patent number
US07608621B2

Reaction notes

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