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

HRID 48956ノート

反応式

HRID 48956 の反応式
[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

参加物

6

反応物 4

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

生成物 1

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

試薬・触媒・溶媒 1

HCID 702Ethanol溶媒2 回

反応条件

温度
80 °C

実験手順

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.

後処理

  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.)

出典と根拠

ORDレコード
ord-9b22bce1e76d4819815d7ce903e55614
出典データセット
uspto-grants-2004_03
特許番号
US06706710B2

反応ノート

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