Hydrochloric Acid → (R)-1-(1-(2-(diethylamino)ethyl)piperidin-3-yl)-6-(6-(3-ethylureido)-4-(4-phenylthiazol-2-yl)pyridin-3-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylic acid

HRID 1047134Notes

Reaction equation

HRID 1047134 reaction equation
[CH2:1]([NH:3][C:4](=[O:26])[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]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[CH:7]=1)[CH3:2].Br[C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][N:37]=1)[N:34]([C@@H:38]1[CH2:43][CH2:42][CH2:41][N:40]([CH2:44][CH2:45][N:46]([CH2:49][CH3:50])[CH2:47][CH3:48])[CH2:39]1)[CH:33]=[C:32]([C:51]([O:53]CC)=[O:52])[C:31]2=[O:56].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Li+].Cl>O1CCOCC1.O.C1(P([Pd-4](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)C=CC=CC=1>[CH2:49]([N:46]([CH2:47][CH3:48])[CH2:45][CH2:44][N:40]1[CH2:41][CH2:42][CH2:43][C@@H:38]([N:34]2[C:35]3[C:30](=[CH:29][C:28]([C:9]4[CH:10]=[N:11][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:26])=[CH:7][C:8]=4[C:15]4[S:16][CH:17]=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[N:19]=4)=[N:37][CH:36]=3)[C:31](=[O:56])[C:32]([C:51]([OH:53])=[O:52])=[CH:33]2)[CH2:39]1)[CH3:50]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 10796Cesium carbonateHCID 594161886-(3-Ethylureido)-4-(4-phenylthiazol-2-yl)pyridin-3-ylboronic acidHCID 86665040(R)-ethyl 6-bromo-1-(1-(2-(diethylamino)ethyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate

Product 1

HCID 49833087(R)-1-(1-(2-(diethylamino)ethyl)piperidin-3-yl)-6-(6-(3-ethylureido)-4-(4-phenylthiazol-2-yl)pyridin-3-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylic acidYield 36%

Reagents, catalysts & solvents 3

HCID 178420553HCID 178420553, compoundCatalystHCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 6-(3-ethylureido)-4-(4-phenylthiazol-2-yl)pyridine-3-ylboronic acid (WO2009106885) (624 mg, 1.69, 1 equiv.) and (R)-ethyl 6-bromo-1-(1-(2-(diethylamino)ethyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate Intermediate 65 (765 mg, 1.69 mmol, 1 equiv.) in 1,4-dioxane (7 mL) was added tetrakis(triphenylphosphino)palladium(0) (196 mg, 0.17 mmol, 0.1 equiv.) followed by a solution of cesium carbonate (828 mg, 2.54 mmol, 2.0 equiv.) in water (1.7 mL). This reaction mixture was stirred at 100° C. for 2 h. 2 M Lithium hydroxide (0.96 mL) was added. The reaction mixture was stirred at 100° C. for 9 h, cooled to room temperature, and diluted with water. 1 N HCl was added until pH 3-4 was reached, and the reaction was concentrated. The compound was purified (C18 silica gel chromatography) and concentrated to provide (R)-1-(1-(2-(diethylamino)ethyl)piperidin-3-yl)-6-(6-(3-ethylureido)-4-(4-phenylthiazol-2-yl)pyridin-3-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylic acid (422.1 mg, 36%). Calcd for C37H42N8O4S [M+H]+: 695.3.

Workup

  1. stirringThe reaction mixture was stirred at 100° C. for 9 h
  2. temperaturecooled to room temperature
  3. concentrationthe reaction was concentrated
  4. customThe compound was purified (C18 silica gel chromatography) and
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-4ce97214e2c846e2b869308c28f52a61
Source dataset
uspto-grants-2013_10
Patent number
US08569484B2

Reaction notes

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