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 2425089Notes

Reaction equation

HRID 2425089 reaction equation
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]

Participants

7

Reactant 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

Product 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

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6212ChloroformSolvent

Conditions

Temperature
70 °C

Procedure

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: C20H22Cl2N2O6S 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%.

Workup

  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)

Sources & evidence

ORD record
ord-38b88dba89774d6e92fe813403709f1b
Source dataset
uspto-grants-2011_06
Patent number
US07964631B2

Reaction notes

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