Citric Acid → HCID 178427848, compound

HRID 1617787Notes

Reaction equation

HRID 1617787 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[CH3:28])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[NH:29]1[C:33]([C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)=[N:32][N:31]=[N:30]1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.C(OCC)(=O)C.O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([C:37]3[CH:36]=[CH:35][C:34]([C:33]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:39][CH:38]=3)=[CH:7][CH:6]=2)[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[C:22]([CH3:28])[CH:23]=1

Participants

9

Reactant 4

HCID 311Citric AcidHCID 10340Sodium CarbonateHCID 58043184HCID 58043184, compoundHCID 178514828HCID 178514828, compound

Product 1

HCID 178427848HCID 178427848, compound

Reagents, catalysts & solvents 4

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of (E)-5-(3-(4-bromophenyl)-3-(4-fluoro-2-methylphenyl)-1-(hydroxyimino)propyl)-1-methylpyridin-2(1H)-one (0.1 g, example 224) in dioxane (1 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane adduct (CAS RN: [95464-05-4]) (9.21 mg), 4-(1H-tetrazol-5-yl)phenylboronic acid (64.3 mg, CAS RN: [179942-55-3]), water (0.65 mL) and aqueous 2M sodium carbonate solution (338 μL) and the reaction mixture was heated for 23 hours at 80° C. The reaction mixture was poured on 10% aqueous citric acid solution and ethyl acetate and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography using a MPLC system (20 g silica gel column, CombiFlash Companion, Isco Inc.) eluting with a gradient of dichloromethane:methanol (100:0 to 75:25). The product was purified a second time by preparative HPLC (phenomenex gemini column) with a gradient of acetonitrile:water (containing 0.5% formic acid) (10:90 to 98:2) to yield the title compound containing 10% of the corresponding Z isomer as as a white foam, MS (ESI+): m/z=509.21 [M+H]+.

Workup

  1. customthe layers were separated
  2. extractionThe aqueous layer was extracted twice with ethyl acetate
  3. dry with materialThe combined organic layers were dried over magnesium sulfate
  4. filtrationfiltered
  5. additiontreated with silica gel
  6. customevaporated
  7. customThe compound was purified by silica gel chromatography
  8. washeluting with a gradient of dichloromethane:methanol (100:0 to 75:25)
  9. customThe product was purified a second time by preparative HPLC (phenomenex gemini column) with a gradient of acetonitrile

Sources & evidence

ORD record
ord-a4d021bc87ef4eb5860e56afeeaa3b21
Source dataset
uspto-grants-2014_07
Patent number
US08765730B2

Reaction notes

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