Hydrochloric Acid → 2-(4-Dimethylaminomethyl-3-fluoro-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one

HRID 33327

反応式

HRID 33327 の反応式
[F:1][C:2]1[CH:9]=[C:8]([C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[C:22](=[O:23])[NH:21][CH2:20][CH2:19][C:18]=2[C:17]=34)[CH:7]=[CH:6][C:3]=1[CH:4]=O.Br[C:25]1C=CC(C=O)=C(F)C=1.[C:34]([BH3-])#[N:35].[Na+].Cl>CNC.CO.[Cl-].[Zn+2].[Cl-]>[CH3:25][N:35]([CH2:4][C:3]1[CH:6]=[CH:7][C:8]([C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[C:22](=[O:23])[NH:21][CH2:20][CH2:19][C:18]=2[C:17]=34)=[CH:9][C:2]=1[F:1])[CH3:34]

参加物

8

反応物 4

HCID 313Hydrochloric AcidHCID 1435174-Bromo-2-fluorobenzaldehydeHCID 5003444Sodium cyanoborohydrideHCID 222666772-Fluoro-4-(6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzaldehyde

生成物 1

HCID 222666892-(4-Dimethylaminomethyl-3-fluoro-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one

試薬・触媒・溶媒 3

HCID 3007855Zincchloride触媒HCID 674Dimethylamine溶媒HCID 887Methanol溶媒2 回

実験手順

2-Fluoro-4-(6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzaldehyde (72 mg, 0.23 mmol. Prepared via the standard two-step, one-pot suzuki coupling of the tricyclic bromide and 4-bromo-2-fluoro-benzaldehyde as described for Example YY) was dissolved in 2 mL 2.0 M dimethylamine in methanol. The orange solution was stirred at room temperature 10 min. The reaction was then cooled to 0° C. and a solution containing zinc chloride (17 mg, 0.13 mmol) and sodium cyanoborohydride (16 mg, 0.26 mmol) in 1 mL methanol, was added dropwise. The pH was adjusted to ca. 3 with concentrated HCl. The reaction was stirred for one hour as the temperature gradually warmed to room temperature. The reaction was partitioned between CHCl3 and water. The pH of the aqueous layer was adjusted to ca. 13 with solid KOH. The layers were separated, and the aqueous layer extracted with 25% iPrOH/CHCl3. The combined organic layers were dried (MgSO4) then concentrated in vacuo. Radial chromatography (eluting with 5% MeOH/CHCl3) then crystallization from CH2Cl2/hexanes yielded 2-(4-dimethylaminomethyl-3-fluoro-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 60 mg (76%) as a yellow solid.: m.p. 221.5-222.5° C.; 1H NMR (300 MHz, d6-DMSO) δ 2.19 (s, 6H), 3.08 (m, 2H), 3.39 (m, 2H), 3.50 (s, 2H), 7.23 (app t, J=7.8 Hz, 1H), 7.50 (m, 4H), 7.69 (d, J=7.5 Hz, 1H) 8.10 (br t, 1H), 11.62 (br s, 1H). MS (FAB, MH+) 338. Anal. (C20H20FN3O) C, H, N.

後処理

  1. temperatureThe reaction was then cooled to 0° C.
  2. additionwas added dropwise
  3. stirringThe reaction was stirred for one hour as the temperature
  4. temperaturegradually warmed to room temperature
  5. customThe reaction was partitioned between CHCl3 and water
  6. customThe layers were separated
  7. extractionthe aqueous layer extracted with 25% iPrOH/CHCl3
  8. dry with materialThe combined organic layers were dried (MgSO4)
  9. concentrationthen concentrated in vacuo
  10. washRadial chromatography (eluting with 5% MeOH/CHCl3)
  11. customcrystallization from CH2Cl2/hexanes

出典と根拠

ORDレコード
ord-d3756cf170f14e28beb5f4e792c60678
出典データセット
uspto-grants-2008_09
特許番号
US07429578B2

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