1,1'-Carbonyldiimidazole → HCID 59133840, compound

HRID 1994086Notes

Reaction equation

HRID 1994086 reaction equation
[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:40](O)=[O:41])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[CH:25]=[CH:24][S:23][C:22]=4[C:26]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])=[CH:18][C:17]4[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:55][N:56]([CH3:61])[S:57]([NH2:60])(=[O:59])=[O:58].C1CCN2C(=NCCC2)CC1.CNS(NC)(=O)=O>C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:40]([NH:60][S:57](=[O:59])(=[O:58])[N:56]([CH3:61])[CH3:55])=[O:41])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[CH:25]=[CH:24][S:23][C:22]=4[C:26]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])=[CH:18][C:17]4[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1

Participants

7

Reactant 5

HCID 682631,1'-CarbonyldiimidazoleHCID 811841,8-Diazabicyclo(5.4.0)undec-7-ene2×HCID 89736N,N'-DimethylsulfamideHCID 134472N,N-DimethylsulfamideHCID 59133838HCID 59133838, compound

Product 1

HCID 59133840HCID 59133840, compoundYield 31.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

In a 2 dram vial, dissolve 13-Cyclohexyl-3-methoxy-6-(2-(4-morpholinylcarbonyl)-3-thienyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (38 mg, 0.065 mmol) in 1 mL of anhydrous THF, add CDI (19.03 mg, 0.117 mmol) to the reaction. The reaction was capped under a nitrogen atmosphere and stirred at room temperature for approximately 1 hour. The reaction was heated capped under nitrogen at 65 C for 1 hour, then cooled to room temperature and N,N-Dimethylsulfamide (44.3 mg, 0.357 mmol) then DBU (13.8 μL, 0.092 mmol) added to the reaction. The reaction was capped and heated under nitrogen over night at 65° C. Analysis of an aliquot by LC-MS indicated that the reaction was incomplete. To the reaction was added more dimethylsulfamide (19 mg, 0.153 mmol) and DBU (13.8 uL, 0.092 mmol). The reaction was capped under a nitrogen atmosphere and heated at 69 C for 3.25 hrs. Analysis of the reaction by LC-MS indicated that the reaction was complete. The reaction was partitioned between dichloromethane and 1N aqueous hydrochloric acid. The aqueous layer was extracted with dichloromethane. The organic layers were combined and washed sequentially with 1N aqueous hydrochloric acid then 0.1M sodium dihydrogen phosphate (NaH2PO4) and dried over sodium sulfate. Volatiles were removed in vacuuo to give a yellow oil/film. The crude title compound was dried in vacuuo overnight at room temperature. Weight of crude product is 43 mg as a yellow/brown solid. Dissolve in a mixture of acetonitrile and DMF and purify by reverse phase HPLC under the following conditions: Shimadzu Preparative HPLC running Discovery VP software, % A=10% acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1% TFA; Initial % B=50; Final % B=100; Gradient=15 min; Runtime=25 min; Flow rate=25 ml/min; Wavelength=220 nm; Column=Waters Sunfire 19 mm×100 mm. Product collection time=9.72 min. to 10.49 min. Volatiles were removed in vacuuo from the product fraction to yield 14.2 mg of the title compound as a yellow solid. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.17-1.30 (m, 1H) 1.32-1.50 (m, 2H) 1.55 (d, J=11.29 Hz, 1H) 1.78 (d, J=10.99 Hz, 2H) 1.90-2.16 (m, 4 H) 2.42-2.58 (m, 1H) 2.60-2.86 (m, 4H) 2.85-2.94 (m, 2H) 2.95-3.04 (m, 2H) 3.06 (s, 6H) 3.10-3.30 (m, 1H) 3.91 (s, 3H) 4.56 (d, J=14.65 Hz, 1H) 5.09 (d, J=14.65 Hz, 1H) 6.87 (s, 1H) 6.93 (d, J=2.75 Hz, 1H) 7.05 (dd, J=8.70, 2.59 Hz, 1 H) 7.08 (d, J=4.88 Hz, 1H) 7.45 (d, J=4.88 Hz, 1H) 7.47-7.54 (m, 2H) 7.83 (s, 1H) 7.91 (d, J=8.55 Hz, 1H) 9.59 (s, 1H). LC-MS: Shimadzu Analytical HPLC using Discovery VP software: % A=5% acetonitrile, 95% water, 10 mmol Ammonium Acetate % B=95% acetonitrile, 5% water, 10 mmol Ammonium Acetate; Initial % B=0; Final % B=100; Gradient=3 min; Runtime=4 min; Flow rate=5 ml/min; Wavelength=220 nm; Column=Waters Xterra, 3 mm×50 mm, S7. Retention Time=2.05 min min, MS m/z 689 (MH+), m/z 687 (M−H)−.

Workup

  1. customto the reaction
  2. customThe reaction was capped under a nitrogen atmosphere
  3. temperatureThe reaction was heated
  4. customcapped under nitrogen at 65 C for 1 hour
  5. temperaturecooled to room temperature
  6. customThe reaction was capped
  7. temperatureheated under nitrogen over night at 65° C
  8. customThe reaction was capped under a nitrogen atmosphere
  9. temperatureheated at 69 C for 3.25 hrs
  10. customAnalysis of the reaction by LC-MS
  11. customThe reaction was partitioned between dichloromethane and 1N aqueous hydrochloric acid
  12. extractionThe aqueous layer was extracted with dichloromethane
  13. washwashed sequentially with 1N aqueous hydrochloric acid
  14. dry with material0.1M sodium dihydrogen phosphate (NaH2PO4) and dried over sodium sulfate
  15. customVolatiles were removed in vacuuo
  16. customto give a yellow oil/film
  17. dry with materialThe crude title compound was dried in vacuuo overnight at room temperature
  18. dissolutionDissolve in a mixture of acetonitrile and DMF
  19. custompurify by reverse phase HPLC under the following conditions
  20. customGradient=15 min
  21. customRuntime=25 min
  22. customProduct collection time=9.72 min. to 10.49 min
  23. customVolatiles were removed in vacuuo from the product fraction

Sources & evidence

ORD record
ord-e7f965e3dec9435bbe019d978af2e67c
Source dataset
uspto-grants-2010_01
Patent number
US07652004B2

Reaction notes

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