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Triethylamine → Methyl 5-(3-(4-((3-(tert-butoxycarbonyl)azetidin-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-(pyridin-2-yl)isoxazole-4-carboxylate

HRID 1951953
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Reaktionsgleichung

Reaktionsgleichung von HRID 1951953
[CH3:1][O:2][C:3]([C:5]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:7][O:8][C:9]=1[C:10]([OH:12])=O)=[O:4].O[N:20]=[C:21]([C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)[NH2:22].N1C=CC=CC=1C1C(C(F)(F)F)=C(C2ON=C(C3C=CC(CN4CC(C(O)=O)C4)=CC=3)N=2)ON=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>CN(C)C=O>[C:35]([O:34][C:32]([CH:30]1[CH2:31][N:28]([CH2:27][C:26]2[CH:39]=[CH:40][C:23]([C:21]3[N:22]=[C:10]([C:9]4[O:8][N:7]=[C:6]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=5)[C:5]=4[C:3]([O:2][CH3:1])=[O:4])[O:12][N:20]=3)=[CH:24][CH:25]=2)[CH2:29]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
KomponentenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

7

Edukt 5

HCID 8471TriethylamineHCID 152842Bis(2-oxo-3-oxazolidinyl)phosphinic chlorideHCID 468359141-(4-(5-(3-(Pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acidHCID 580628354-(Methoxycarbonyl)-3-(pyridin-2-yl)isoxazole-5-carboxylic acidHCID 76806751tert-butyl 1-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]azetidine-3-carboxylate

Produkt 1

HCID 66677904Methyl 5-(3-(4-((3-(tert-butoxycarbonyl)azetidin-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-(pyridin-2-yl)isoxazole-4-carboxylateAusbeute 48,6 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6228DimethylformamideLösungsmittel

Versuchsvorschrift

To a mixture of 4-(methoxycarbonyl)-3-(pyridin-2-yl)isoxazole-5-carboxylic acid (79 mg, 0.318 mmol), tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int. 1 (97 mg, 0.318 mmol), and BOP—Cl (97 mg, 0.382 mmol) in dimethylformamide (1.5 mL) at room temperature was added triethylamine (0.133 mL, 0.955 mmol). The reaction mixture was allowed to stir at room temperature overnight. Some uncyclized material remained, so stirring was continued for an additional 24 hrs. At this time, the reaction mixture was partitioned between ethyl acetate (30 mL) and a saturated aqueous solution of sodium bicarbonate (30 mL). The organic layer was washed with water (2×30 mL), washed with brine (30 mL), and dried over anhydrous magnesium sulfate. Concentration afforded a brown oil that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-70% EtOAc/Hex gradient. The essentially pure fractions containing product were concentrated to afford methyl 5-(3-(4-((3-(tert-butoxycarbonyl)azetidin-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-(pyridin-2-yl)isoxazole-4-carboxylate (80 mg, 0.155 mmol, 48.6% yield) as a light purple solid. HPLC retention time=2.91 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=518.20.

Aufarbeitung

  1. stirringso stirring
  2. waitwas continued for an additional 24 hrs
  3. customAt this time, the reaction mixture was partitioned between ethyl acetate (30 mL)
  4. washThe organic layer was washed with water (2×30 mL)
  5. washwashed with brine (30 mL)
  6. dry with materialdried over anhydrous magnesium sulfate
  7. concentrationConcentration
  8. customafforded a brown oil that
  9. customwas chromatographed on a 4 gm Isco silica gel cartridge
  10. washeluting with a 0-70% EtOAc/Hex gradient
  11. additionThe essentially pure fractions containing product
  12. concentrationwere concentrated

Quellen und Nachweise

ORD-Eintrag
ord-3dd6ff701a884ef0b9338b66429ea814
Quelldatensatz
uspto-grants-2013_03
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08404672B2

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