Acetic Acid → Methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylate

HRID 1854825Notes

Reaction equation

HRID 1854825 reaction equation
N1CCCCC1.C(O)(=O)C.[CH3:11][C:12]1[C:13]([CH:19]([CH:22]2[CH2:24][CH2:23]2)[CH:20]=O)=[N:14][CH:15]=[CH:16][C:17]=1[Cl:18].[C:25](OC)(=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28]>C(O)C>[Cl:18][C:17]1[CH:16]=[CH:15][N:14]2[C:13]([C:12]=1[CH3:11])=[C:19]([CH:22]1[CH2:24][CH2:23]1)[CH:20]=[C:26]([C:27]([O:29][CH3:30])=[O:28])[C:25]2=[O:31]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 7943Dimethyl malonateHCID 8082PiperidineHCID 186293552-(3-Methyl-4-chloro-pyridin-2-yl)-2-cyclopropyl-acetaldehyde

Product 1

HCID 86696543Methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylate

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
100 °C

Procedure

Piperidine (7 mL, 70.9 mmol) and acetic acid (5.5 mL, 95 mmol) were added to a solution of 2-(3-methyl-4-chloro-pyridin-2-yl)-2-cyclopropyl-acetaldehyde (4.98 g, 23.75 mmol) in absolute ethanol (200 mL). Dimethyl malonate (16.44 mL, 144 mmol) was added and the reaction mixture was stirred at 100° C. for 5 h (the reaction mixture turned into a red solution). The solvent was evaporated under reduced pressure. The resulting mixture was diluted with ether (100 mL) and washed with water (100 mL) and brine (50 mL). The organic layer was separated and dried over sodium sulfate. The mixture was evaporated to dryness. Dowtherm A (110 mL) was added. This reaction mixture was heated to 240° C. under microwave irradiation and stirred at this temperature for 0.5 h during which the reaction mixture turned into a black solution. The residue was purified by reversed phase flash chromatography using a 5%-100% acetonitrile gradient in water with 1% TFA yielding the cyclized methyl ester (4 g, 51.4%). ESI-MS m/z: 292 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm: 9.34 (d, J=7.8 Hz, 1H), 8.42 (s, 1H), 7.13 (d, J=7.8 Hz, 1H), 3.95 (s, 1H), 3.01 (s, 1H), 2.35-2.27 (m, 1H), 1.03-1.08 (m, 2H), 0.72-0.76 (m, 2H); 13C NMR (100 MHz CDCl3) δ ppm 166.6, 155.4, 148.4, 145.5, 142.3, 130.7, 129.0, 117.6, 115.6, 105.4, 52.3, 19.6, 17.0, 9.9 (2CH2).

Workup

  1. customThe solvent was evaporated under reduced pressure
  2. additionThe resulting mixture was diluted with ether (100 mL)
  3. washwashed with water (100 mL) and brine (50 mL)
  4. customThe organic layer was separated
  5. dry with materialdried over sodium sulfate
  6. customThe mixture was evaporated to dryness
  7. additionDowtherm A (110 mL) was added
  8. temperatureThis reaction mixture was heated to 240° C. under microwave irradiation
  9. stirringstirred at this temperature for 0.5 h during which the reaction mixture
  10. customThe residue was purified by reversed phase flash chromatography

Sources & evidence

ORD record
ord-d5f903cdf35b49dcaaca754a410f8233
Source dataset
uspto-grants-2015_02
Patent number
US08962842B2

Reaction notes

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