Potassium Iodide → HCID 11287642, compound

HRID 1785956Notes

Reaction equation

HRID 1785956 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22]([C:24]3[CH:25]=[N:26]N(C(C)C)C=3)=[O:23])[C@@H:14]([CH3:32])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([N:36]1[CH:40]=[C:39]([C:41](Cl)=[O:42])C=N1)(C)C.Br[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47].[C:51](=[O:54])([O-])[O-:52].[K+].[K+].[I-].[K+].CN([CH:62]=[O:63])C>O>[C:9]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@H:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]([C:41]2[O:42][N:36]=[C:40]([O:52][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH:39]=2)=[O:23])[C@@H:14]([CH3:32])[CH2:13]1)(=[O:11])[CH3:10].[CH2:41]([O:42][C:62](=[O:63])[CH2:51][O:54][C:25]1[CH:24]=[C:22]([C:46]([O:48][CH3:49])=[O:47])[O:23][N:26]=1)[CH3:39]

Participants

9

Reactant 6

HCID 4875Potassium IodideHCID 6228DimethylformamideHCID 7748Ethyl bromoacetateHCID 11430Potassium CarbonateHCID 11510715HCID 11510715, compoundHCID 60136483HCID 60136483, compound

Product 2

HCID 11287642HCID 11287642, compoundYield 60%HCID 86601698HCID 86601698, compound

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

Ethyl [(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}isoxazol-3-yl)oxy]acetate was prepared following the procedure for N-(4-chlorophenyl)-N-{(2S,4R)-1-[(1-isopropyl-1H-pyrazol-4-yl)carbonyl]-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl}acetamide substituting ethyl {[5-(chlorocarbonyl)isoxazol-3-yl]oxy}acetate for 1-isopropyl-1H-pyrazole-4-carbonyl chloride. (Ethyl {[15-chlorocarbonyl)isoxazol-3-yl]oxy}acetate was prepared in 4 steps from methyl 3-hydroxy 5-isoxazole carboxylate. Methyl 3-hydroxy 5-isoxazole carboxylate (1.00 g, 6.95 mmol) was alkylated using ethyl bromoacetate (0.850 mL, 7.64 mmol) in presence of potassium carbonate (1.05 g, 7.64 mmol) and catalytic potassium iodide in DMF (3.00 mL) at room temperature overnight. Water was added to the reaction mixture and extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired methyl 3-(2-ethoxy-2-oxoethoxy)isoxazole-5-carboxylate (60%). (Ref: WO 03/063800 PCT/US03/03224). Methyl 3-(2-ethoxy-2-oxoethoxy)isoxazole-5-carboxylate was further treated with aqueous 5% sodium hydroxide in methanol to yield 3-(carboxymethoxy)isoxazole-5-carboxylic acid (86%). This diacid (0.700 g, 3.76 mmol) was selectively esterified in the presence of catalytic p-toluenesulfonic acid monohydrate (100 mg) in ethanol at room temperature. Water was added to the reaction and the mixture was extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired 3-(2-ethoxy-2-oxoethoxy)isoxazole-5-carboxylic acid (90%). 3-(2-Ethoxy-2-oxoethoxy)isoxazole-5-carboxylic acid was treated with oxalyl chloride and catalytic DMF in dichloromethane to yield the desired ethyl {[5-(chlorocarbonyl)isoxazol-3-yl]oxy}acetate). Ethyl [(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}isoxazol-3-yl)oxy]acetate was treated with a solution of lithium hydroxide monohydrate (aq) in methanol at room temperature overnight to afford [(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}isoxazol-3-yl)oxy]acetic acid in 60% yield.

Workup

  1. customat room temperature
  2. customovernight
  3. extractionextracted with ethyl acetate
  4. washThe organics were washed with brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-2b7043dea18c49ecaa89891f8f1cfd79
Source dataset
uspto-grants-2009_03
Patent number
US07504508B2

Reaction notes

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