Methanol → 4-Chloro-2-(4-cyclopropyl-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester

HRID 1927506Notes

Reaction equation

HRID 1927506 reaction equation
[CH:1]1([NH2:4])[CH2:3][CH2:2]1.Cl[CH2:6][CH2:7][N:8]([CH2:31][CH2:32]Cl)[C:9]1[CH:29]=[C:28]([Cl:30])[C:12]2[O:13][C:14]3[C:23]([CH3:24])=[CH:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][C:15]=3[S:16](=[O:19])(=[O:18])[CH2:17][C:11]=2[CH:10]=1.[CH3:34]O>>[CH3:34][O:27][C:25]([C:21]1[CH:22]=[C:23]([CH3:24])[C:14]2[O:13][C:12]3[C:28]([Cl:30])=[CH:29][C:9]([N:8]4[CH2:7][CH2:6][N:4]([CH:1]5[CH2:3][CH2:2]5)[CH2:32][CH2:31]4)=[CH:10][C:11]=3[CH2:17][S:16](=[O:19])(=[O:18])[C:15]=2[CH:20]=1)=[O:26]

Participants

4

Reactant 3

HCID 887MethanolHCID 69828CyclopropylamineHCID 1317284742-[Bis-(2-chloroethyl)amino]-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cycloheptene-8-carboxylic acid

Product 1

HCID 1317284884-Chloro-2-(4-cyclopropyl-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester

Conditions

Temperature
110 °C

Procedure

Cyclopropyl amine (0.819 g, 14.34 mmol) was added to a solution of Example 102j (0.5 g, 1.04 mmol) in methanol (5 mL), followed by addition of n-tetrabutylammonium iodide (0.010 g, 0.027 mmol) in an atmosphere of nitrogen, in a pressure reactor vessel and heated at 110° C. for 10 h. It was brought to room temperature, concentrated, treated with methanolic HCl solution, and refluxed at 70° C. for 2 h. The reaction mixture was concentrated, treated with aqueous sodium bicarbonate solution to neutral pH and extracted with n-butanol. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, 5% methanol/chloroform) to obtain the title compound. Yield: 0.220 g, (45%); 1H NMR (DMSO-d6): δ 0.4 (m, 4H, 2CH2), 1.65 (m, 1H, CH), 2.7 (s, 3H, CH3), 2.80 (d, 4H, 2CH2), 3.10 (m, 4H, 2CH2), 3.90 (s, 3H, OCH3), 5.2 (s, 2H, CH2), 7.05 (s, 1H, Ar), 7.1 (s, 1H, Ar), 8.1 (s, 1H, Ar), 8.15 (s, 1H, Ar); MS: m/e (EI+) 447 (M+).

Workup

  1. customwas brought to room temperature
  2. concentrationconcentrated
  3. additiontreated with methanolic HCl solution
  4. temperaturerefluxed at 70° C. for 2 h
  5. concentrationThe reaction mixture was concentrated
  6. additiontreated with aqueous sodium bicarbonate solution to neutral pH
  7. extractionextracted with n-butanol
  8. washThe organic layer was washed with water, brine
  9. customdried
  10. concentrationconcentrated
  11. custompurified

Sources & evidence

ORD record
ord-474df3b895874c85849a783d97920379
Source dataset
uspto-grants-2012_05
Patent number
US08183234B2

Reaction notes

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