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

HRID 1173358Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1173358
N.[Cl:2]CC[N:5](CCCl)C1C=C(Cl)C2OC3C(C)=CC(C(O)=O)=CC=3S(=O)(=O)CC=2C=1.[CH3:31][O:32][C:33]([C:35]1[CH:36]=[C:37]([CH3:60])[C:38]2[O:44][C:43]3[C:45]([Cl:56])=[CH:46][C:47]([N:49]([CH2:53][CH2:54]Cl)[CH2:50][CH2:51]Cl)=[CH:48][C:42]=3[CH2:41][S:40](=[O:58])(=[O:57])[C:39]=2[CH:59]=1)=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>CO.C(Cl)(Cl)Cl>[ClH:2].[CH3:31][O:32][C:33]([C:35]1[CH:36]=[C:37]([CH3:60])[C:38]2[O:44][C:43]3[C:45]([Cl:56])=[CH:46][C:47]([N:49]4[CH2:50][CH2:51][NH:5][CH2:54][CH2:53]4)=[CH:48][C:42]=3[CH2:41][S:40](=[O:57])(=[O:58])[C:39]=2[CH:59]=1)=[O:34]

Komponenten

7

Edukt 4

HCID 222AmmoniaHCID 10340Sodium CarbonateHCID 115260722-[Bis-(2-chloro-ethyl)-amino]-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl esterHCID 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

Produkt 1

HCID 116052774-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cycloheptene-8-carboxylic acid methyl ester hydrochloride

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 887MethanolLösungsmittelHCID 6212ChloroformLösungsmittel

Reaktionsbedingungen

Temperatur
70 °C

Versuchsvorschrift

Aqueous ammonia solution (25%, 300 mL) was added to 2-[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 (52 g, 0.109 mol) [prepared by alkaline hydrolysis of compound of Example 12] in methanol (100 mL). The reaction mixture was sealed under nitrogen atmosphere, kept at 110° C. for 9 h, cooled and the seal was opened. The reaction mixture was concentrated to remove solvent and ammonia, and azeotroped with toluene. The product was taken in methanolic HCl solution (300 mL) and stirred at 70° C. for 9 h. The reaction mixture was cooled, solid separated was filtered, washed with methanol and dried under vacuum to obtain the crude product. The crude product was dissolved in chloroform and treated with aqueous sodium carbonate to obtain the free base, which was purified by column chromatography (silica gel, 5% methanol in chloroform) to obtain freebase of the title compound. Yield: 32 g (68%). This was converted to the hydrochloride salt using methanolic HCl. mp: 277-280° C.; 1H NMR (DMSO-d6, 300 MHz): δ 2.66 (s, 3H, CH3), 3.19 (m, 4H, 2CH2), 3.40 (m, 4H, 2CH2), 3.85 (s, 3H, OCH3), 5.10 (s, 2H, CH2), 7.10 (s, 1H, Ar), 7.20 (s, 1H, Ar), 8.05 (s, 1H, Ar) and 8.20 (s, 1H, Ar); MS: m/e (ES+) 437 (M+1, free base); analysis: C20H22Cl2N2O5S requires C, 50.75; H, 4.68; N, 5.92; Cl, 14.98; S, 6.77. found: C, 50.85; H, 4.62; N, 6.14; Cl, 15.30; S, 6.80%.

Aufarbeitung

  1. customThe reaction mixture was sealed under nitrogen atmosphere
  2. temperaturecooled
  3. concentrationThe reaction mixture was concentrated
  4. customto remove solvent and ammonia
  5. customazeotroped with toluene
  6. temperatureThe reaction mixture was cooled
  7. customsolid separated
  8. filtrationwas filtered
  9. washwashed with methanol
  10. customdried under vacuum
  11. customto obtain the crude product
  12. customto obtain the free base, which
  13. customwas purified by column chromatography (silica gel, 5% methanol in chloroform)

Quellen und Nachweise

ORD-Eintrag
ord-3566c9a026a246c5843193e110344581
Quelldatensatz
uspto-grants-2010_11
Patentnummer
US07834052B2

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