Triethylamine → (5)-1-(4-(1-methyl-7-(3-methylmorpholino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-3-(oxetan-3-yl)urea

HRID 72190

Reaktionsgleichung

Reaktionsgleichung von HRID 72190
[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9]2[N:25]([CH3:26])[N:24]=[CH:23][C:10]=2[N:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[N:13]=1.C(N(CC)CC)C.Cl[C:35](Cl)([O:37]C(=O)OC(Cl)(Cl)Cl)Cl.Cl.[O:47]1[CH2:50][CH:49]([NH2:51])[CH2:48]1>ClCCCl.CCOC(C)=O>[CH3:26][N:25]1[C:9]2[C:8]([N:3]3[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]3[CH3:1])=[N:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:35]([NH:51][CH:49]4[CH2:50][O:47][CH2:48]4)=[O:37])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH:23]=[N:24]1

Komponenten

7

Edukt 4

HCID 8471TriethylamineHCID 94429TriphosgeneHCID 23062080Oxetan-3-amine hydrochlorideHCID 58222489(S)-3-methyl-4-(1-methyl-5-(4-nitrophenyl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl)morpholine

Produkt 1

HCID 51355347(5)-1-(4-(1-methyl-7-(3-methylmorpholino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-3-(oxetan-3-yl)ureaAusbeute 75,6 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 111,2-DichloroethaneLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
0 °C

Versuchsvorschrift

To a stirred solution of (S)-3-methyl-4-(1-methyl-5-(4-nitrophenyl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl)morpholine (50.0 mg, 0.154 mmol) in anhydrous 1,2-dichoroethane (5.0 mL) was added triethylamine (0.071 mL, 0.51 mmol, 3.3 eq.). The reaction was cooled to 0° C. and triphosgene (45.7 mg, 0.154 mmol, 1.0 eq) was added in one portion. After stirring at 0° C. under N2 for 5 minutes, the reaction mixture was stirred at 70° C. for 1 h. The reaction mixture was cooled to RT, and 3-oxetanamine hydrochloride (84.4 mg, 0.77 mmol, 5.0 eq.) was then added. The reaction mixture was stirred at RT under N2 for 16 h and then diluted with EtOAc (25 mL). The organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified by column chromotagraphy (Si-PPC, gradient 50 to 100% EtOAc in heptane, followed by 0 to 30% methanol in dichloromethane). Trituration from methanol afforded the title compound (49.3 mg, 75.5%) as a solid. 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.76 (s, 1H), 8.25 (d, J=8.8 Hz, 2H), 8.21 (s, 1H), 7.50 (d, J=8.8 Hz, 2H), 6.97 (d, J=6.7 Hz, 1H), 4.85 to 4.69 (m, 3H), 4.44 (t, J=6.0 Hz, 2H), 4.23 to 4.12 (m, 4H), 3.96 to 3.81 (m, 2H), 3.72 (dd, J=14.7 Hz, 5.8 Hz, 1H), 3.69 to 3.58 (m, 2H), 3.50 (d, J=13.3 Hz, 1H), 1.26 (d, J=6.5 Hz, 3H); LC-MS m/z (method C1)=424.2 [M+H]+, RT=3.12 min.

Aufarbeitung

  1. stirringthe reaction mixture was stirred at 70° C. for 1 h
  2. temperatureThe reaction mixture was cooled to RT
  3. stirringThe reaction mixture was stirred at RT under N2 for 16 h
  4. washThe organic layer was washed with water and brine
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude was purified by column chromotagraphy (Si-PPC, gradient 50 to 100% EtOAc in heptane, followed by 0 to 30% methanol in dichloromethane)

Quellen und Nachweise

ORD-Eintrag
ord-c3413a6d73644ad6805a0f4fcc8e642a
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08828990B2

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