반응 #77234

반응 방정식

imidazole

HBr

acetic acid

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

→

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

수율 92.0%

용매

ethanol

ethanol

반응 조건

후처리

1. 1
   workup.ADDITIONAfter the addition of all the material
2. 2
   workup.DISSOLUTIONis dissolved
3. 3
   여과the solution is filtered clear
4. 4
   온도The reaction mixture is then cooled to 65° C.
5. 5
   workup.ADDITIONA are added
6. 6
   기타From 65° C.
7. 7
   기타is −10° C
8. 8
   여과are filtered off
9. 9
   세척washed with cool ethanol
10. 10
    기타Drying under vacuum (50° C.)

실험 절차

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.

출처