Dimethyl Sulfoxide → 7-Chloro-9-(4-methyl-piperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-carbaldehyde

HRID 2415732Notes

Reaction equation

HRID 2415732 reaction equation
C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[C:21]([CH2:22][OH:23])=[C:20]([CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[C:19]2[CH:18]=[C:17]3[O:32][CH2:33][CH2:34][O:35][C:16]3=[CH:15][C:14]=2[N:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[C:21]([CH:22]=[O:23])=[C:20]([CH2:24][N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)[C:19]2[CH:18]=[C:17]3[O:32][CH2:33][CH2:34][O:35][C:16]3=[CH:15][C:14]=2[N:13]=1

Participants

6

Reactant 4

HCID 679Dimethyl SulfoxideHCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 22637071[7-Chloro-9-(4-methylpiperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-yl]-methanol

Product 1

HCID 226370787-Chloro-9-(4-methyl-piperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-carbaldehyde

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
-58 °C

Procedure

A 3-necked 4-L round-bottom flask is equipped with a mechanical stirrer and a 250-mL addition funnel. Under nitrogen, the flask is charged with methylene chloride (800 mL), followed by addition of oxalyl chloride (28.8 mL, 330 mmol). The solution is cooled to −78° C. arid dimethyl sulfoxide (46.7 mL, 660 mmol) is added over 6 min. The temperature of the solution increases to −58° C. during the addition and is cooled back to about −70° C. After stirring for 3 min, [7-chloro-9-(4-methylpiperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-methanol (100 g, 275 mmol), as prepared above, is added as a solution in 140 mL of methylene chloride over 10 min. The yellow slurry is stirred for 45 min, then anhydrous triethylamine (153 mL, 1.10 mol) is added over 4 min. Stirring is continued for 10 min at −78° C., then the cooling bath is removed. The reaction mixture is allowed to warm to −5° C. and poured into 2 L of water. The organic layer is separated and the aqueous layer is extracted with methylene chloride (3×1.5 L). The combined organic layers are washed with brine (2 L), dried over anhydrous sodium sulfate and concentrated in vacuo yielding 7-chloro-9-(4-methylpiperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-carbaldehyde as a dark solid. This crude product is used for the next step without further purification. Recrystallization from CH2Cl2-MeOH (5:1) provided an analytical sample as a light yellow solid: 140-142° C. (dec.). 1H NMR (CDCl3, 200 MHz) d 2.30 (s, 3H), 2.45, 2.59 (m, 8H) 3.98 (s, 2H). 4.41 (s, 4H), 7.46 (s, 1H), 7.53 (s, 1H), 10.4 (s, 1H). Elemental analysis: Calculated for C18H20ClN3O3: C 59.75, H 5.57, N 11.61. Found: C 59.78, H 5.62, N 11.64.

Workup

  1. customA 3-necked 4-L round-bottom flask is equipped with a mechanical stirrer and a 250-mL addition funnel
  2. additionis added over 6 min
  3. temperatureis cooled back to about −70° C
  4. stirringThe yellow slurry is stirred for 45 min
  5. stirringStirring
  6. waitis continued for 10 min at −78° C.
  7. customthe cooling bath is removed
  8. temperatureto warm to −5° C.
  9. additionpoured into 2 L of water
  10. customThe organic layer is separated
  11. extractionthe aqueous layer is extracted with methylene chloride (3×1.5 L)
  12. washThe combined organic layers are washed with brine (2 L)
  13. dry with materialdried over anhydrous sodium sulfate
  14. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-991db56b24de4f0eb49e296ab79b204e
Source dataset
uspto-grants-2004_11
Patent number
US06821982B2

Reaction notes

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