Acetic Acid → (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide

HRID 48956Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 48956
[CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[C:8]2[C:3]=1[CH2:4][CH2:5][C@@H:6]([NH:19][C:20](=[O:33])[C:21]1[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=1)[CH2:7]2.N1C=CN=C1.[BrH:39].C(O)(=O)C>C(O)C>[BrH:39].[CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[C:8]2[C:3]=1[CH2:4][CH2:5][C@@H:6]([NH:19][C:20](=[O:33])[C:21]1[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=1)[CH2:7]2

Komponenten

6

Edukt 4

HCID 176Acetic AcidHCID 260Hydrogen BromideHCID 795ImidazoleHCID 9846516AR-A000002

Produkt 1

HCID 9936785(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromideAusbeute 92 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 702EthanolLösungsmittel2×

Reaktionsbedingungen

Temperatur
80 °C

Versuchsvorschrift

To a slurry of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide in ethanol (493 g, 1.1 mole, 2.5 L) is added a mixture of imidazole (82 g, 1.2 mole) and HBr in acetic acid (33 w/w %, 124 g, 1.5 mole) in ethanol (2.5 L) at 65° C. After the addition of all the material is dissolved, the solution is filtered clear and then heated at 80° C. for 2 h. The reaction mixture is then cooled to 65° C. and seeding crystals of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide Form A are added. From 65° C. a cooling profile is started with a cooling rate of 7-8° C./h until the temperature is −10° C. The slurry is then stirred for 8 hrs at −10° C. before the crystals are filtered off and washed with cool ethanol. Drying under vacuum (50° C.) gives 533 g (92%) of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide Form A; 1H NMR (300 MHz, DMSO-d6) δ 8.24 (d, J=7.5 Hz, 1 H), 7.86 (d, J=8 Hz, 2 H), 6.92-7.08 (m, 1 H), 7.01 (d, J=7.5 Hz, 1 H), 6.98 (d, J=8 Hz, 1 H), 6.86 (d, J=8 Hz, 1 H), 3.61-4.07 (m, 5 H), 2.42-3.61 (m, 16 H), 2.84 (s, 3 H), 2.00-2.20 (m, 1 H), 2.15 (s, 3 H), 1.63-1.88 (m, 1 H). For further characterization, see below.

Aufarbeitung

  1. additionAfter the addition of all the material
  2. dissolutionis dissolved
  3. filtrationthe solution is filtered clear
  4. temperatureThe reaction mixture is then cooled to 65° C.
  5. additionA are added
  6. customFrom 65° C.
  7. customis −10° C
  8. filtrationare filtered off
  9. washwashed with cool ethanol
  10. customDrying under vacuum (50° C.)

Quellen und Nachweise

ORD-Eintrag
ord-9b22bce1e76d4819815d7ce903e55614
Quelldatensatz
uspto-grants-2004_03
Patentnummer
US06706710B2

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