Triethylamine → Piperidin-4-yl8-carbamoyl-6-(3-methoxyphenyl)-9H-carbazol-2-ylcarbamate

HRID 2410690Notes

Reaction equation

HRID 2410690 reaction equation
[C:1]([C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12](C(O)=O)[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].C([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.OC1CC[N:56]([C:59]([O:61][C:62](C)(C)C)=[O:60])CC1>O1CCOCC1.C(OCC)(=O)C>[NH:30]1[CH2:31][CH2:32][CH:62]([O:61][C:59](=[O:60])[NH:56][C:12]2[CH:11]=[CH:10][C:9]3[C:8]4[C:16](=[C:4]([C:1](=[O:3])[NH2:2])[CH:5]=[C:6]([C:20]5[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=5)[CH:7]=4)[NH:15][C:14]=3[CH:13]=2)[CH2:34][CH2:33]1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 199401P,P-Diphenylphosphinic azideHCID 643502Tert-butyl 4-hydroxypiperidine-1-carboxylateHCID 666057668-carbamoyl-6-(3-methoxyphenyl)-9H-carbazole-2-carboxylic acid

Product 1

HCID 66604933Piperidin-4-yl8-carbamoyl-6-(3-methoxyphenyl)-9H-carbazol-2-ylcarbamate

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

To a suspension of 8-carbamoyl-6-(3-methoxyphenyl)-9H-carbazole-2-carboxylic acid (36 mg, 0.100 mmol, Example 82B) and 4 A° molecular sieves (36 mg) in 1,4-dioxane (1.5 mL) at 50° C. was added triethylamine (0.034 mL, 0.247 mmol) and diphenylphosphoryl azide (70.0 mg, 0.247 mmol). The mixture was stirred for 1.5 h and at that point tert-butyl 4-hydroxypiperidine-1-carboxylate (201 mg, 0.999 mmol) was added. The reaction mixture was stirred at 80° C. for 5 h. The reaction was cooled, diluted with ethyl acetate, and filtered. The solvent was removed from the filtrate and the Boc-protected product was isolated by preparative HPLC (100×30 mm Luna C18 column, flow rate 42 ml permin, gradient elution starting with A:B=80:20 and ending with A:B=0:100 [A=10 mM NH4OAc in 5% aqueous acetonitrile; B=10 mM NH4OAc in 95% aqueous acetonitrile] over 20 min) followed by removal of the solvents. It was treated with a mixture of DCM (6 mL) and TFA (3 mL) at rt for 2 h. The solvent was removed and the crude product was purified by preparative HPLC (100×30 mm Luna C18 column, flow rate 42 ml permin, gradient elution starting with A:B=90:10 and ending with A:B=30:70 [A=10 mM NH4OAc in 5% aqueous acetonitrile; B=10 mM NH4OAc in 95% aqueous acetonitrile] over 20 min) The HPLC fractions that contained the product were applied onto a cartridge of PHENOMENEX® Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with 2 N solution of ammonia in methanol. Removal of the solvents left 29.4 mg of piperidin-4-yl 8-carbamoyl-6-(3-methoxyphenyl)-9H-carbazol-2-ylcarbamate as a solid. MS (ESI) m/z 459.2 (M+H). 1H NMR (MeOD) δ ppm 8.40 (1H, s), 8.11 (1H, s), 8.04 (1H, d, J=8.55 Hz), 7.88 (1H, br. s.), 7.30-7.43 (3H, m), 7.15-7.27 (2H, m), 6.86-6.97 (1H, m), 3.89 (3H, s), 3.37 (1H, s), 3.04-3.14 (2H, m), 2.67-2.80 (2H, m), 2.00 (2H, dd, J=9.00, 4.12 Hz), 1.63-1.74 (2H, m).

Workup

  1. additionwas added
  2. temperatureThe reaction was cooled
  3. filtrationfiltered
  4. customThe solvent was removed from the filtrate
  5. customwas isolated by preparative HPLC (
  6. wash100×30 mm Luna C18 column, flow rate 42 ml permin, gradient elution
  7. customB=10 mM NH4OAc in 95% aqueous acetonitrile] over 20 min) followed by removal of the solvents
  8. additionIt was treated with a mixture of DCM (6 mL) and TFA (3 mL) at rt for 2 h
  9. customThe solvent was removed
  10. customthe crude product was purified by preparative HPLC (
  11. wash100×30 mm Luna C18 column, flow rate 42 ml permin, gradient elution
  12. waitB=10 mM NH4OAc in 95% aqueous acetonitrile] over 20 min) The HPLC fractions that contained
  13. additionmixed-mode polymer
  14. washThis was washed with methanol and product
  15. washwas eluted with 2 N solution of ammonia in methanol
  16. customRemoval of the solvents
  17. waitleft 29.4 mg of piperidin-4-yl 8-carbamoyl-6-(3-methoxyphenyl)-9H-carbazol-2-ylcarbamate as a solid

Sources & evidence

ORD record
ord-60399a8195b64f6fb81199d37a58d3a4
Source dataset
uspto-grants-2014_08
Patent number
US08815840B2

Reaction notes

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