Water → methyl 4-(1-(3,4-dichlorophenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamido)tetrahydro-2H-pyran-4-carboxylate

HRID 2421896

Reaktionsgleichung

Reaktionsgleichung von HRID 2421896
[ClH:1].[NH2:2][C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[Si](C=[N+]=[N-])(C)(C)[CH3:13].[OH2:19].[C:20]1([S:26]([N:29]2[CH2:34][CH2:33][O:32][C:31]3[N:35]=[CH:36][C:37]([C:39](N4CCCCC4)=[O:40])=[CH:38][C:30]2=3)(=O)=[O:27])[CH:25]=[CH:24]C=[CH:22][CH:21]=1.[CH2:47]([Cl:49])Cl>CCOCC.C([O-])(O)=O.[Na+]>[Cl:1][C:24]1[CH:25]=[C:20]([S:26]([N:29]2[CH2:34][CH2:33][O:32][C:31]3[N:35]=[CH:36][C:37]([C:39]([NH:2][C:3]4([C:9]([O:11][CH3:13])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]4)=[O:40])=[CH:38][C:30]2=3)(=[O:27])=[O:19])[CH:21]=[CH:22][C:47]=1[Cl:49]

Komponenten

8

Edukt 5

HCID 962Water2×HCID 6344DichloromethaneHCID 167693TrimethylsilyldiazomethaneHCID 27344004-Aminotetrahydro-2H-pyran-4-carboxylic acid hydrochlorideHCID 44242653(1-(phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)(piperidin-1-yl)methanone2×

Produkt 1

HCID 44241782methyl 4-(1-(3,4-dichlorophenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamido)tetrahydro-2H-pyran-4-carboxylateAusbeute 33,3 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 3283Diethyl EtherLösungsmittelHCID 516892Sodium BicarbonateLösungsmittel

Versuchsvorschrift

To a suspension of 4-amino-tetrahydro-pyran-4-carboxylic acid hydrochloride (53.5 mg, 0.294 mmol) in Et2O (1 mL) was added TMS-diazomethane (0.392 mL, 0.785 mmol) and water (200 μL). Upon addition of water, a vigorous evolution of gas occurred. The reaction was allowed to stir for 10 min at which time the reaction turned clear. The excess TMS-diazomethane was quenched by addition of AcOH until the solution turned colorless. The reaction mixture was concentrated in vacuo to provide an aqueous solution. The aqueous solution was added to a biphasic mixture of 1-(3,4-dichloro-phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonyl chloride (80 mg, 0.196 mmol, prepared from Intermediate O by analogy with Example 1) in DCM (4 mL) and saturated aqueous NaHCO3 (4 mL). The reaction was allowed to stir for 16 h. The biphasic mixture was extracted with DCM (3×5 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo. The resulting solid was purified by flash column chromatography using a gradient elution of hexanes with 10-70% EtOAc to provide methyl 4-(1-(3,4-dichlorophenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamido)tetrahydro-2H-pyran-4-carboxylate (36.5 mg, 0.065 mmol, 33.3% yield) as a white solid. LCMS (+ESI) m/z=530.0 [M+H]+; 1H-NMR (CDCl3) δ 8.53 (s, 1H), 8.50 (br s, 1H), 7.83, (d, 1H), 7.59 (d, 1H), 7.49 (dd, 1H), 6.34 (br s, 1H), 4.10 (m, 2H), 3.89 (m, 4H), 3.80 (s, 3H), 3.75 (m, 2H), 2.35 (m, 2H), 2.10 (m, 1H), 2.07 (m 1H).

Aufarbeitung

  1. customThe excess TMS-diazomethane was quenched by addition of AcOH until the solution
  2. concentrationThe reaction mixture was concentrated in vacuo
  3. customto provide an aqueous solution
  4. stirringto stir for 16 h
  5. extractionThe biphasic mixture was extracted with DCM (3×5 mL)
  6. dry with materialThe combined organics were dried over Na2SO4
  7. concentrationconcentrated in vacuo
  8. customThe resulting solid was purified by flash column chromatography
  9. washa gradient elution of hexanes with 10-70% EtOAc

Quellen und Nachweise

ORD-Eintrag
ord-bfa21bc15e7d4a61b2be35996d7a5154
Quelldatensatz
uspto-grants-2011_06
Patentnummer
US07960377B2

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