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Dimethylformamide → N-(2-Dimethylamino-ethyl)-2-hydroxy-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-methyl-benzamide

HRID 901489
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 901489
CO[C:3](=[O:38])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[CH:17][N:16](S(C4C=CC(C)=CC=4)(=O)=O)[C:13]3=[N:14][CH:15]=2)[CH:7]=[CH:6][C:5]=1[OH:37].[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][NH:43][CH3:44].N=C=N.CN(C=O)C>N1C=CC=CC=1>[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][N:43]([CH3:44])[C:3](=[O:38])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[CH:17][NH:16][C:13]3=[N:14][CH:15]=2)[CH:7]=[CH:6][C:5]=1[OH:37]
KomponentenReaktionsbedingungenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

6

Edukt 4

HCID 6228DimethylformamideHCID 673381,2-Ethanediamine, N1,N1,N2-trimethyl-HCID 160435CarbodiimideHCID 596997122-Hydroxy-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid methyl ester

Produkt 1

HCID 16039312N-(2-Dimethylamino-ethyl)-2-hydroxy-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-methyl-benzamide
Ausbeute 12 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 1049PyridineLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

To a solution of 2-hydroxy-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid methyl ester (52 mg, 0.10 mmol) in pyridine (0.5 mL) was added an excess of N,N,N′-trimethylethylenediamine (0.5 mL). The reaction was stirred for 16 hours at 100° C. in a scintillation vial. There appeared to be ˜50% product formation and ˜50% hydrolysis of the methyl ester to the carboxylic acid. PS-carbodiimide resin (244 mg, 0.29 mmol, 1.21 mmol/g load capacity) and DMF (1 mL) were added to the reaction solution and heating was continued for 16 hours at 70° C. The resin was filtered off and rinsed well with THF and MeOH. The filtrate was concentrated down to a yellow oil and then redissolved in a 1:1 MeOH/acetone solution (4 mL total). The solution was treated with 200 uL of a 50% KOH (aq) solution and stirred at ambient temperature for 3 hours. Glacial acetic acid was added dropwise until the pH=7. The product was extracted into ethyl acetate, whereupon the organic layer was washed with H2O, dried over Na2SO4, filtered, and concentrated under vacuum. The material was dissolved in MeOH and filtered through a 0.45 μm syringe filter. The solution was purified by reverse phase chromatography using a gradient of H2O and acetonitrile (with 0.1% formic acid as a modifier). Clean fractions were lyophilized, affording the title compound as a white powder (5.2 mg, 12% yield). 1H NMR (500 MHz, d6-DMSO) δ 11.80 (d, J=2.5 Hz, 1H), 8.49 (s, 1H), 8.19 (s, 1H), 8.10 (s, 1H), 7.74 (d, J=2.5 Hz, 1H), 7.63 (dd, J=2.0, 6.0 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.43 (s, 1H), 7.33 (m, 1H), 7.17 (d, J=8.5 Hz, 1H), 7.09 (t, J=6.5 Hz, 1H), 7.01 (d, J=9.0 Hz, 1H), 3.85 (s, 3H), 3.01 (br s, 3H), 2.90 (br s, 2H), 2.59 (m, 2H), 2.36 (br s, 3H), 2.00 (br s, 3H). MS: m/z 445.1 (M+H+).

Aufarbeitung

  1. temperatureheating
  2. waitwas continued for 16 hours at 70° C
  3. filtrationThe resin was filtered off
  4. washrinsed well with THF and MeOH
  5. concentrationThe filtrate was concentrated down to a yellow oil
  6. dissolutionredissolved in a 1:1 MeOH/acetone solution (4 mL total)
  7. additionThe solution was treated with 200 uL of a 50% KOH (aq) solution
  8. stirringstirred at ambient temperature for 3 hours
  9. additionGlacial acetic acid was added dropwise until the pH=7
  10. extractionThe product was extracted into ethyl acetate, whereupon the organic layer
  11. washwas washed with H2O
  12. dry with materialdried over Na2SO4
  13. filtrationfiltered
  14. concentrationconcentrated under vacuum
  15. dissolutionThe material was dissolved in MeOH
  16. filtrationfiltered through a 0.45 μm syringe
  17. filtrationfilter
  18. customThe solution was purified by reverse phase chromatography

Quellen und Nachweise

ORD-Eintrag
ord-17a48046c608413dbd4031ece761e051
Quelldatensatz
uspto-grants-2008_04
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US07361764B2

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