1,2-Dichloroethane → tert-butyl {2-{[(7R)-14-cyclohexyl-11-[({[(2,2-dimethoxyethyl)(methyl)amino]sulfonyl}amino)carbonyl]-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocin-7-yl}(methyl)amino]ethyl}carbamate

HRID 1669397Notes

Reaction equation

HRID 1669397 reaction equation
[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:40])[C@@H:12]1[CH2:19][N:18]2[C:20]3[CH:21]=[C:22]([C:33](O)=[O:34])[CH:23]=[CH:24][C:25]=3[C:26]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[C:17]2[C:16]2[CH:36]=[CH:37][CH:38]=[CH:39][C:15]=2[O:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[CH3:45][O:46][CH:47]([O:55][CH3:56])[CH2:48][N:49]([CH3:54])[S:50]([NH2:53])(=[O:52])=[O:51].S(N)(N)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH:27]1([C:26]2[C:25]3[CH:24]=[CH:23][C:22]([C:33]([NH:53][S:50]([N:49]([CH2:48][CH:47]([O:46][CH3:45])[O:55][CH3:56])[CH3:54])(=[O:52])=[O:51])=[O:34])=[CH:21][C:20]=3[N:18]3[C:17]=2[C:16]2[CH:36]=[CH:37][CH:38]=[CH:39][C:15]=2[O:14][CH2:13][C@H:12]([N:11]([CH3:40])[CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:19]3)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1

Participants

8

Reactant 4

HCID 111,2-Dichloroethane2×HCID 82267SulfamideHCID 66674687(7R)-7-[{2-[(tert-butoxycarbonyl)amino]ethyl}(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acidHCID 86627889N-(2,2-dimethoxyethyl)-N-methylsulfamide

Product 1

HCID 86627890tert-butyl {2-{[(7R)-14-cyclohexyl-11-[({[(2,2-dimethoxyethyl)(methyl)amino]sulfonyl}amino)carbonyl]-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocin-7-yl}(methyl)amino]ethyl}carbamateYield 44%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
40 °C

Procedure

To a solution of (7R)-7-[{2-[(tert-butoxycarbonyl)amino]ethyl}(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (0.15 M) in DCM were added sequentially EDC (1.8 eq), N-(2,2-dimethoxyethyl)-N-methylsulfamide (1.8 eq) (prepared as described in Step 1) and DMAP (1.2 eq). The mixture was stirred at 40° C. for 1.5 hours. Further EDC (0.48 eq) and sulfamide (0.5 eq) were introduced and heating continued for 1 h. The reaction was left to cool with stirring overnight. The reaction was diluted with EtOAc and washed with 1N HCl (aq). The aqueous was extracted with EtOAc and the organics combined, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to leave a brown gum. The residue was purified by RP-HPLC (Waters Xterra column; MeCN/H2O/0.1% TFA gradient). Fractions containing the pure compound were combined and lyophilized to afford the product as a white powder (44%). MS (ES+) m/z 728 (M+H)+.

Workup

  1. temperatureheating
  2. waitcontinued for 1 h
  3. waitThe reaction was left
  4. temperatureto cool
  5. stirringwith stirring overnight
  6. washwashed with 1N HCl (aq)
  7. extractionThe aqueous was extracted with EtOAc
  8. washwashed with brine
  9. dry with materialdried (Na2SO4)
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customto leave a brown gum
  13. customThe residue was purified by RP-HPLC (Waters Xterra column; MeCN/H2O/0.1% TFA gradient)
  14. additionFractions containing the pure compound

Sources & evidence

ORD record
ord-91e96d27f3bd4906b1e8d7f8b549fc8c
Source dataset
uspto-grants-2011_08
Patent number
US07989438B2

Reaction notes

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