Hydrochloric Acid → 10-(tert-butoxycarbonyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid

HRID 1994087Notes

Reaction equation

HRID 1994087 reaction equation
[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([O:23]C)=[O:22])=[CH:18][C:17]4[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl.P([O-])(O)(O)=O.[Na+]>C1COCC1.CO.CN(C=O)C>[C:34]([O:33][C:31]([C:11]1[CH:10]=[CH:9][C:8]2[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:15]3[C:16]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:17]=4[CH:18]=[C:19]([C:21]([OH:23])=[O:22])[CH2:20][N:14]3[C:13]=2[CH:12]=1)=[O:32])([CH3:37])([CH3:35])[CH3:36]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 2723671Tetrabutylammonium HydroxideHCID 23672064Monosodium phosphateHCID 5983755810-tert-butyl 6-methyl 13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate

Product 1

HCID 5771220210-(tert-butoxycarbonyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

Dissolve 10-(1,1-dimethylethyl) 6-methyl 13-cyclohexyl-3-(methyloxy)-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate (5.53 g, 11.02 mmol) in THF (70 ml) with heating, add DMF (20 ml) to maintain solubility, allow to cool to room temperature then add tetrabutylammonium hydroxide (33.1 ml, 33.1 mmol) 1.0M in methanol. Stir reaction at room temperature for 2 hrs then add 0.1N aqueous 0.1N hydrochloric acid to the reaction followed by 01M aqueous NaH2PO4. Separate phases, wash organic layer sequentially with 1.0N aqueous hydrochloric acid, 0.1M aqueous NaH2PO4. Back extract aqueous 1× using ethyl acetate. Combine ethyl acetate fractions and wash sequentially with 0.1M aqueous NaH2PO4 and brine. Dry over magnesium sulfate, filter and remove solvents in vacuuo to yield a bright yellow solid. Dry product in vacuuo at room temperature to give 5.21 g (97%). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.12-1.28 (m, 2 H) 1.28-1.45 (m, 2H) 1.46-1.60 (m, 2H) 1.63 (s, 9H) 1.66-1.96 (m, 4H) 1.96-2.16 (m, 3H) 2.76-2.84 (m, 1H) 3.91 (s, 3H) 4.18 (br.s., 1H) 5.66 (br.s, 1H) 7.00 (d, J=2.44 Hz, 1H) 7.10 (dd, J=8.55, 2.75 Hz, 1H) 7.53 (d, J=8.54 Hz, 1H) 7.65-7.71 (m, 1H) 7.82 (d, J=8.24 Hz, 1H) 7.93 (s, 1H) 8.22 (s, 1H). LC-MS retention time 1.47 min; 486 m/z (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

Workup

  1. temperaturewith heating
  2. temperatureto maintain solubility
  3. customreaction at room temperature for 2 hrs
  4. washSeparate phases, wash organic layer sequentially with 1.0N aqueous hydrochloric acid, 0.1M aqueous NaH2PO4
  5. extractionBack extract aqueous 1×
  6. washCombine ethyl acetate fractions and wash sequentially with 0.1M aqueous NaH2PO4 and brine
  7. dry with materialDry over magnesium sulfate
  8. filtrationfilter
  9. customremove solvents in vacuuo
  10. customto yield a bright yellow solid
  11. customDry product in vacuuo at room temperature to give 5.21 g (97%)
  12. washThe elution conditions
  13. customa gradient time of 2 min
  14. customa hold time of 1 min
  15. customan analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B

Sources & evidence

ORD record
ord-1e542675b38149f5a7d74989a8d786dc
Source dataset
uspto-grants-2010_01
Patent number
US07652004B2

Reaction notes

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