Hydrochloric Acid → 7-Iodo-9-(4-methylpiperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-carbaldehyde

HRID 357516Notes

Reaction equation

HRID 357516 reaction equation
O.Cl[C:3]1[C:12]([CH:13]=[O:14])=[C:11]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[C:10]2[CH:9]=[C:8]3[O:23][CH2:24][CH2:25][O:26][C:7]3=[CH:6][C:5]=2[N:4]=1.[I-:27].[Na+].Cl>C(#N)C>[I:27][C:3]1[C:12]([CH:13]=[O:14])=[C:11]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[C:10]2[CH:9]=[C:8]3[O:23][CH2:24][CH2:25][O:26][C:7]3=[CH:6][C:5]=2[N:4]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 962WaterHCID 5238Sodium IodideHCID 226370787-Chloro-9-(4-methyl-piperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-carbaldehyde

Product 1

HCID 226370757-Iodo-9-(4-methylpiperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-carbaldehyde

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

A 4-necked 12-L round-bottom flask is equipped with a mechanical stirrer and water-cooled condenser. Under nitrogen, the flask is charged with 7-chloro-9-(4-methyl-piperazin-1-yl-methyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-carbaldehyde (120 g, 346 mmol), prepared as in example 13f, sodium iodide (1.04 kg, 6.92 mmol), and 3 L of acetonitrile. To the yellow suspension is added concentrated hydrogen chloride (59.7 mL, 726 mmol) over 5 min. The white slurry is refluxed for 15 hr. The solvent is mostly removed by short-path distillation in vacuo. The resultant thick slurry is cooled to ambient temperature and treated with 2.5 L of water and 2.5 L of methylene chloride. The organic layer is separated and the aqueous layer is extracted with methylene chloride (3×2 L). The combined organic layers are washed with brine (2.5 L), dried over anhydrous sodium sulfate, concentrated and dried in vacuo at 30° C. yielding 7-iodo-9-(4-methyl-piperazin-1-yl-methyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-carbaldehyde as a yellow solid. This crude product is used for the next step without further purification. Recrystallization from CH2Cl2 --MeOH (1:1) gave an analytical sample as an off-white solid: 198°-200° C. (dec.). 1H NMR (CDCl3, 200 MHz) δ2.30 (s, 3H), 2.43, 2.57 (m, 8H), 3.93 (s, 2H). 4.40(s, 4H), 7.47 (s, 1H), 7.50 (s, 1H), 10.1 (s, 1H). Elemental analysis: Calculated for C18H20IN3O3 : C 47.70, H 4.45, N 9.27. Found: C 47.78, H 4.45, N 9.26.

Workup

  1. customA 4-necked 12-L round-bottom flask is equipped with a mechanical stirrer
  2. temperatureThe white slurry is refluxed for 15 hr
  3. customThe solvent is mostly removed by short-path distillation in vacuo
  4. additiontreated with 2.5 L of water and 2.5 L of methylene chloride
  5. customThe organic layer is separated
  6. extractionthe aqueous layer is extracted with methylene chloride (3×2 L)
  7. washThe combined organic layers are washed with brine (2.5 L)
  8. dry with materialdried over anhydrous sodium sulfate
  9. concentrationconcentrated
  10. customdried in vacuo at 30° C.

Sources & evidence

ORD record
ord-c85a156e24074a5683ad440ce1dbf06e
Source dataset
uspto-grants-1998_11
Patent number
US05840898

Reaction notes

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