Lithium Hydroxide → HCID 68747249, compound

HRID 1047133Notes

Reaction equation

HRID 1047133 reaction equation
[CH2:1]([NH:3][C:4](=[O:45])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[N:20][C:21]=2F)[N:18]([C@@H:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:24][OH:25])[CH:17]=[C:16]([C:30]([O:32]CC)=[O:31])[C:15]3=[O:35])=[C:8]([C:36]2[S:37][CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[N:40]=2)[CH:7]=1)[CH3:2].[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[OH-].[Li+].CS(O)(=O)=O>C1COCC1.O>[CH2:1]([NH:3][C:4](=[O:45])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[N:20][C:21]=2[N:50]2[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]2)[N:18]([C@@H:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:24][OH:25])[CH:17]=[C:16]([C:30]([OH:32])=[O:31])[C:15]3=[O:35])=[C:8]([C:36]2[S:37][CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[N:40]=2)[CH:7]=1)[CH3:2]

Participants

7

Reactant 4

HCID 3939Lithium HydroxideHCID 6395Methanesulfonic AcidHCID 531671-MethylpiperazineHCID 69621182HCID 69621182, compound

Product 1

HCID 68747249HCID 68747249, compoundYield 22%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of (S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-7-fluoro-1-(1-hydroxy-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate Intermediate 76 (200 mg, 0.31 mmol, 1 equiv.) in THF (1.2 mL) was added 1-methylpiperazine (0.041 mL, 0.37 mmol, 1.2 equiv.). This reaction was stirred at 50° C. for 10 h. 2 M lithium hydroxide (0.307 mL) was added. The reaction was stirred at 50° C. for 2 h, cooled to room temperature, and diluted with water. 10% wt. sol. of methanesulfonic acid was added until pH 5-6 was reached. The precipitate was discarded. The solution was partitioned between water (10 mL) and ethyl acetate (10 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL), and the aqueous layer was concentrated. The compound was purified (HPLC) and concentrated to provide (S)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxy-3,3-dimethylbutan-2-yl)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid as a solid (52.8 mg, 22%). Calcd for C32H37F3N8O5S [M+H]+: 703.2. H1NMR (d6-DMSO) δ 15.18 (s, 1H), 9.51 (s, 1H), 8.8 (d, 1H), 8.51 (s, 1H), 8.48 (s, 1H), 8.36 (s, 1H), 8.2 (s, 1H), 7.6 (m, 1H), 5.71-5.68 (m, 1H), 5.09-5.02 (m, 1H), 4.09-4.0 (m, 2H), 3.29-3.27 (m, 2H), 3.21-3.19 (m, 2H), 3.15-3.04 (m, 2H), 2.18-2.14 (m, 2H), 2.05 (s, 3H), 1.95-1.91 (m, 2H), 1.12 (t, 3H), 0.95 (s, 9H).

Workup

  1. stirringThe reaction was stirred at 50° C. for 2 h
  2. temperaturecooled to room temperature
  3. customThe solution was partitioned between water (10 mL) and ethyl acetate (10 mL)
  4. extractionThe aqueous layer was extracted with ethyl acetate (2×20 mL)
  5. concentrationthe aqueous layer was concentrated
  6. customThe compound was purified (HPLC)
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-24b10ccbb6bb4f2686b907511fd43e8e
Source dataset
uspto-grants-2013_10
Patent number
US08569484B2

Reaction notes

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