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1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → (3R*,4S*)-tert-butyl 4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-3-fluoropiperidine-1-carboxylate

HRID 2241422
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Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 2241422
CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23]([C:26]([OH:28])=O)=[CH:22][CH:21]=[N:20]2)=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C.[CH3:38][O:39][C:40]1[CH:79]=[CH:78][C:43]([CH2:44][N:45]2[C:49]3=[N:50][CH:51]=[CH:52][C:53]([O:54][C:55]4[CH:60]=[CH:59][C:58]([NH2:61])=[CH:57][C:56]=4[F:62])=[C:48]3[C:47]([NH:63][C@H:64]3[CH2:69][CH2:68][N:67]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:66][C@H:65]3[F:77])=[N:46]2)=[CH:42][CH:41]=1.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:38][O:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:44][N:45]2[C:49]3=[N:50][CH:51]=[CH:52][C:53]([O:54][C:55]4[CH:60]=[CH:59][C:58]([NH:61][C:26]([C:23]5[C:24](=[O:25])[N:19]([C:16]6[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=6)[N:20]=[CH:21][CH:22]=5)=[O:28])=[CH:57][C:56]=4[F:62])=[C:48]3[C:47]([NH:63][C@H:64]3[CH2:69][CH2:68][N:67]([C:70]([O:72][C:73]([CH3:76])([CH3:74])[CH3:75])=[O:71])[CH2:66][C@H:65]3[F:77])=[N:46]2)=[CH:78][CH:79]=1
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Komponenten

7

Edukt 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide2×HCID 757711-HydroxybenzotriazoleHCID 81531Diisopropylethylamine2×HCID 667671712-(4-Fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid2×HCID 68516487(3R*,4S*)-tert-butyl 4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-3-fluoropiperidine-1-carboxylate

Produkt 1

HCID 68515739(3R*,4S*)-tert-butyl 4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-3-fluoropiperidine-1-carboxylateAusbeute 39 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6344DichloromethaneLösungsmittel2×

Versuchsvorschrift

EDCI (43.6 mg, 0.227 mmol) was added to a stirred mixture of 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (53.2 mg, 0.227 mmol, prepared according to the procedure for Example 19, Step C), HOBt-hydrate (34.8 mg, 0.227 mmol) and DIEA (0.0792 ml, 0.455 mmol) in DCM (1 mL) at ambient temperature, and the reaction mixture was stirred for 15 minutes at ambient temperature. ±(3R*,4S*)-tert-Butyl 4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-3-fluoropiperidine-1-carboxylate (66 mg, 0.114 mmol) was then added. The resulting solution was stirred for 18 hours at ambient temperature. To a separate 1 dram vial was added an additional equivalent of the 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid, HOBt, DIEA, and EDCI in DCM (0.5 mL). This mixture was stirred for 15 minutes, then added to the original reaction mixture, which was stirred for an additional day at ambient temperature. The crude reaction mixture was loaded directly on to a preparative TLC plate (2 mm thickness) and eluted with 10% MeOH/DCM (Rf=0.70). A second preparative TLC plate (1 mm thickness, Rf=0.17) eluting with 1:1 EtOAc/hexanes was utilized to obtain pure product (35 mg, 39%)

Aufarbeitung

  1. customprepared
  2. customat ambient temperature
  3. stirringThe resulting solution was stirred for 18 hours at ambient temperature
  4. stirringThis mixture was stirred for 15 minutes
  5. additionadded to the original reaction mixture, which
  6. stirringwas stirred for an additional day at ambient temperature
  7. customThe crude reaction mixture
  8. washeluted with 10% MeOH/DCM (Rf=0.70)
  9. washA second preparative TLC plate (1 mm thickness, Rf=0.17) eluting with 1:1 EtOAc/hexanes

Quellen und Nachweise

ORD-Eintrag
ord-c8396453b6d941eeb0e61d9663989e33
Quelldatensatz
uspto-grants-2010_05
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US07723330B2

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