Lithium Hydroxide → 6-(6-(3-Ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-((1-methylpiperidin-4-yl)methyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

HRID 1047111Notes

Reaction equation

HRID 1047111 reaction equation
I[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[CH:7]=[C:6]([C:20]([O:22]CC)=[O:21])[C:5]2=[O:25].[CH2:26]([NH:28][C:29](=[O:49])[NH:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[C:33]([C:40]2[S:41][CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[N:44]=2)[CH:32]=1)[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Li+]>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>[CH2:26]([NH:28][C:29](=[O:49])[NH:30][C:31]1[N:36]=[CH:35][C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[N:10][CH:11]=2)[N:8]([CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:7]=[C:6]([C:20]([OH:22])=[O:21])[C:5]3=[O:25])=[C:33]([C:40]2[S:41][CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[N:44]=2)[CH:32]=1)[CH3:27]

Participants

8

Reactant 4

HCID 3939Lithium HydroxideHCID 10796Cesium carbonateHCID 594161896-(3-Ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid2×HCID 68750415Ethyl 6-iodo-1-((1-methylpiperidin-4-yl)methyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate2×

Product 1

HCID 498334426-(6-(3-Ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-((1-methylpiperidin-4-yl)methyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acidYield 7.4%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
100 °C

Procedure

To a solution of ethyl 6-iodo-1-((1-methylpiperidin-4-yl)methyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 1, 952 mg, 2.32 mmol) and 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 9, 834 mg, 2.32 mmol) in 1,4-dioxane (7.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (268 mg, 0.23 mmol) followed by a solution of cesium carbonate (1.51 g, 4.63 mmol) in water (2 mL). The reaction mixture was stirred at 100° C. for 2 h. 2 M lithium hydroxide (2.32 mL, 4.63 mmol) was then added and the mixture was stirred at 100° C. for 12 h. The reaction mixture was diluted with water, and the precipitate was washed with water and hexanes and then dried. The compound was purified via reverse phase HPLC (C18, 0-95% acetonitrile/water, gradient) and concentrated under reduced pressure to give 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-((1-methylpiperidin-4-yl)methyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid as a light yellow solid (106.1 mg, 7%).

Workup

  1. stirringthe mixture was stirred at 100° C. for 12 h
  2. washthe precipitate was washed with water and hexanes
  3. customdried
  4. customThe compound was purified via reverse phase HPLC (C18, 0-95% acetonitrile/water, gradient)
  5. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-6ba1a98aaaa44881b266f1a53fa1f30b
Source dataset
uspto-grants-2013_10
Patent number
US08569484B2

Reaction notes

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