Carbamate → Apd-668

HRID 31382

Reaktionsgleichung

Reaktionsgleichung von HRID 31382
Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=3[F:21])[N:9]=[CH:10][C:3]=12.C(=O)([O-])N.[CH:26]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])[CH3:27].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH:26]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([O:38][C:2]2[N:7]=[CH:6][N:5]=[C:4]3[N:8]([C:11]4[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=4[F:21])[N:9]=[CH:10][C:3]=23)[CH2:36][CH2:37]1)=[O:31])([CH3:28])[CH3:27]

Komponenten

6

Edukt 4

HCID 276CarbamateHCID 16745126Isopropyl 4-Hydroxypiperidine-1-carboxylateHCID 218976614-Chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidineHCID 23676156Sodium t-butoxide

Produkt 1

HCID 11705608Apd-668Ausbeute 74,4 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 1140TolueneLösungsmittel

Reaktionsbedingungen

Temperatur
12 °C

Versuchsvorschrift

Toluene (1.6 L) was transferred to a 4 L jacketed reaction vessel fitted with a mechanical stirrer, nitrogen inlet and a temperature probe. 4-Chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (7) (97.0 g, 0.297 mol) was added with stirring into the reaction vessel under nitrogen, and a slurry was obtained. The carbamate, 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (5) (66.57 g, 0.356 mol), was added at room temperature. The reactor was cooled to 12° C. and sodium tert-butoxide (37.09 g, 0.386 mol) was added with stirring. The internal temperature gradually increased to 34° C. due to an exotherm. Then the internal temperature was brought down to 23-25° C. The reaction mixture became a thick slurry and was stirred at room temperature for 2.5 h. The precipitate from the reaction mixture was filtered, washed with toluene (250 mL) followed by water (3×500 mL), and vacuum dried overnight at room temperature. The dried solid product was slurried in EtOH (500 mL) at room temperature, filtered, and washed with water (2.5 L) until the filtrate was neutral. The washed solid product was dissolved in refluxing EtOH (1.3 L), and the resulting clear solution was gradually cooled to room temperature. The product (6) crystallized out and was isolated by filtration and dried overnight in a vacuum oven at 40° C., 20 torr to provide 105.5 g of product (6) (74%). HPLC analysis, >99% (purity, by peak area). 1H NMR (Bruker 400 MHz, CDCl3) δ 8.62 (s, 1H, Ar—H), 8.32 (s, 1H, Ar—H), 7.93 (m, 3H, Ar—H), 5.62 (m, 1H, —O—CH—), 4.95 (m, 1H, CH3—CH—CH3), 3.91 (m, 2H, —CH2—), 3.37 (m, 2H, —CH2—), 3.12 (s, 3H, —SO2CH3), 2.09 (m, 2H, —CH2—), 1.87 (m, 2H, —CH2—), 1.27 (d, 6H, J=8 Hz, CH3—CH—CH3); mass spec. (electrospray) m/z 478 (M+H).

Aufarbeitung

  1. customreaction vessel
  2. customfitted with a mechanical stirrer, nitrogen inlet
  3. customa slurry was obtained
  4. stirringwith stirring
  5. temperatureThe internal temperature gradually increased to 34° C. due to an exotherm
  6. customwas brought down to 23-25° C
  7. stirringwas stirred at room temperature for 2.5 h
  8. filtrationThe precipitate from the reaction mixture was filtered
  9. washwashed with toluene (250 mL)
  10. customdried overnight at room temperature
  11. customwas slurried in EtOH (500 mL) at room temperature
  12. filtrationfiltered
  13. washwashed with water (2.5 L) until the filtrate
  14. dissolutionThe washed solid product was dissolved
  15. temperaturein refluxing EtOH (1.3 L)
  16. temperaturethe resulting clear solution was gradually cooled to room temperature
  17. customThe product (6) crystallized out and
  18. customwas isolated by filtration
  19. customdried overnight in a vacuum oven at 40° C.

Quellen und Nachweise

ORD-Eintrag
ord-d6b98752bcd143bbaacf51d4cddb9421
Quelldatensatz
uspto-grants-2008_09
Patentnummer
US07425630B2

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