Sulfuric Acid → 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide

HRID 1881018

Reaktionsgleichung

Reaktionsgleichung von HRID 1881018
Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]=2[N:19]=1.[NH2:20][C:21]1[C:36]([O:37][CH3:38])=[CH:35][C:24]([C:25]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:26])=[C:23]([F:39])[CH:22]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]2[N:19]=[C:2]([NH:20][C:21]3[C:36]([O:37][CH3:38])=[CH:35][C:24]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[O:26])=[C:23]([F:39])[CH:22]=3)[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]

Komponenten

7

Edukt 4

HCID 1118Sulfuric AcidHCID 10340Sodium CarbonateHCID 669272854-amino-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamideHCID 866359002-Chloro-7,7-difluoro-9-isopropyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one

Produkt 1

HCID 579556334-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamideAusbeute 35,3 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 702EthanolLösungsmittelHCID 962WaterLösungsmittel2×

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

2-chloro-7,7-difluoro-9-isopropyl-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (100 mg, 0.344 mmol) and 4-amino-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide (100 mg, 0.355 mmol) were suspended in water (2 mL) and sulfuric acid (118 mg, 1.20 mmol) was added. The reaction mixture was stirred in a closed vial at 100° C. for 18 h, cooled, diluted with water (5 mL) and brought to pH=7 using solid sodium carbonate. The resulting mixture was diluted with ethanol (0.5 mL) and stirred for 5 min. The precipitate was filtered, washed with water (5 mL) and dried in air for 20-30 min. It was then suspended in ethanol (˜10 mL), treated with solid sodium bicarbonate (130 mg) and stirred vigorously for 45 min. The insoluble salts were filtered off and filtrate was concentrated in vacuo. The residue was crystallized from ethanol-water (1:7; 8 mL) and dried in vacuum to afford the title compound as a white solid (65 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (d, J=6.82 Hz, 6 H) 1.49-1.62 (m, 2 H) 1.77 (br. d., 2 H) 1.95 (app. t, J=11.2 Hz, 2 H) 2.15 (s, 3 H) 2.73 (br. d., J=11.12 Hz, 2 H) 3.33 (s, 3 H) 3.71 (m, J=7.83 Hz, 1 H) 3.91 (s, 3 H) 4.07 (t, J=13.52 Hz, 2 H) 4.90 (m, 1 H) 7.19 (d, J=6.57 Hz, 1 H) 7.88 (dd, J=7.33, 3.03 Hz, 1 H) 7.97 (s, 1 H) 8.20-8.32 (m, 2 H); [M+H] calc'd for C25H32F3N7O3, 536; found 536.

Aufarbeitung

  1. temperaturecooled
  2. stirringstirred for 5 min
  3. filtrationThe precipitate was filtered
  4. washwashed with water (5 mL)
  5. customdried in air for 20-30 min
  6. additiontreated with solid sodium bicarbonate (130 mg)
  7. stirringstirred vigorously for 45 min
  8. filtrationThe insoluble salts were filtered off
  9. concentrationfiltrate was concentrated in vacuo
  10. customThe residue was crystallized from ethanol-water (1:7; 8 mL)
  11. customdried in vacuum

Quellen und Nachweise

ORD-Eintrag
ord-2b8409d17a9342ecb341f23adae2b060
Quelldatensatz
uspto-grants-2012_11
Patentnummer
US08318727B2

Verknüpfte Notizen

Wird geladen…