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

HRID 1047129Notes

Reaction equation

HRID 1047129 reaction equation
[CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[N:11]=[CH:10][C:9](B(O)O)=[C:8]([C:15]2[S:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)[CH:7]=1)[CH3:2].Br[C:26]1[CH:27]=[C:28]2[C:33](=[N:34][CH:35]=1)[N:32]([C@H:36]1[CH2:41][CH2:40][CH2:39][N:38]([CH2:42][CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[CH2:37]1)[CH:31]=[C:30]([C:50]([O:52]CC)=[O:51])[C:29]2=[O:55].C([O-])([O-])=O.[Cs+].[Cs+].[Li+].[OH-]>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>[CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:26]2[CH:27]=[C:28]3[C:33](=[N:34][CH:35]=2)[N:32]([CH:36]2[CH2:41][CH2:40][CH2:39][N:38]([CH2:42][CH2:43][N:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)[CH2:37]2)[CH:31]=[C:30]([C:50]([OH:52])=[O:51])[C:29]3=[O:55])=[C:8]([C:15]2[S:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)[CH:7]=1)[CH3:2]

Participants

8

Reactant 4

HCID 3939Lithium HydroxideHCID 10796Cesium carbonateHCID 594161896-(3-Ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid2×HCID 69621275(S)-ethyl 6-bromo-1-(1-(2-morpholinoethyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate2×

Product 1

HCID 687472516-(6-(3-Ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-(2-morpholinoethyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 9, 0.350 g, 0.97 mmol) and (S)-ethyl 6-bromo-1-(1-(2-morpholinoethyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 34, 0.480 g, 0.97 mmol) were taken up in dioxane (4 mL), Cs2CO3 (0.633 g, 1.94 mmol) in water (1.000 mL) was added followed by Pd(PPh3)4 (0.112 g, 0.10 mmol). The reaction mixture was heated to 100° C. for 2 h, then 2 ml of 2N LiOH were added and stirred at 100° C. for an additional 30 min. The reaction mixture was cooled to room temperature and solvent evaporated. The resulting residue was taken back up in DMSO (2 ml) and filtered. DMSO solution was purified on an ISCO C18 column using water and acetonitrile. (S)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-(2-morpholinoethyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (0.080 g, 12%) is recovered as a pale yellow solid.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. customsolvent evaporated
  3. filtrationfiltered
  4. customDMSO solution was purified on an ISCO C18 column
  5. custom(S)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-(2-morpholinoethyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (0.080 g, 12%) is recovered as a pale yellow solid

Sources & evidence

ORD record
ord-063d826c11c647ba9df14757fa08344c
Source dataset
uspto-grants-2013_10
Patent number
US08569484B2

Reaction notes

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