Dimethylformamide → HCID 178502407, compound

HRID 1471063Notes

Reaction equation

HRID 1471063 reaction equation
[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[N:23]=[C:24]([C@@H:27]5[CH2:31][CH2:30][CH2:29][NH:28]5)[NH:25][CH:26]=4)=[CH:18][CH:17]=3)=[N:14][N:13]=[C:12]2[C:32]2[CH:37]=[CH:36][C:35]([C:38]3[N:39]=[C:40]([C@@H:43]4[CH2:47][CH2:46][CH2:45][NH:44]4)[NH:41][CH:42]=3)=[CH:34][CH:33]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:48][O:49][C:50]([NH:52][C@@H:53]([CH:57]([CH3:59])[CH3:58])[C:54](O)=[O:55])=[O:51].[CH:60]1[CH:65]=C2N=NN(O)C2=C[CH:61]=1.[OH2:70].CCN=C=NCCCN(C)C.C[N:83]1[CH2:88][CH2:87][O:86]C[CH2:84]1.CN([CH:92]=[O:93])C>CCOC(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:12]([C:32]3[CH:37]=[CH:36][C:35]([C:38]4[N:39]=[C:40]([C@@H:43]5[CH2:47][CH2:46][CH2:45][N:44]5[C:87](=[O:86])[C@@H:88]([NH:83][C:84]([O:93][CH3:92])=[O:70])[CH:60]([CH3:65])[CH3:61])[NH:41][CH:42]=4)=[CH:34][CH:33]=3)=[N:13][N:14]=[C:15]2[C:16]2[CH:17]=[CH:18][C:19]([C:22]3[N:23]=[C:24]([C@@H:27]4[CH2:31][CH2:30][CH2:29][N:28]4[C:54](=[O:55])[C@@H:53]([NH:52][C:50](=[O:51])[O:49][CH3:48])[CH:57]([CH3:59])[CH3:58])[NH:25][CH:26]=3)=[CH:20][CH:21]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]

Participants

8

Reactant 6

HCID 6228DimethylformamideHCID 79724-MethylmorpholineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 27960291-Hydroxybenzotriazole hydrateHCID 10942966(2S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acidHCID 178440992HCID 178440992, compound

Product 1

HCID 178502407HCID 178502407, compoundYield 65%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

In an oven-dried 5-mL round bottom flask purged with nitrogen, dissolved the product of Example 218E (50 mg, 0.080 mmol) in anhydrous DMF (1 mL), and cooled to 0° C. Added sequentially (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (29.5 mg, 0.168 mmol), HOBt hydrate (27.6 mg, 0.180 mmol), EDAC (35.3 mg, 0.180 mmol), and N-methylmorpholine (0.035 mL, 0.321 mmol). Stirred the solution at 25° C. for 15 hr. Diluted the reaction in EtOAc (50 mL), washed with sat'd aq NaHCO3 (25 mL), H2O (3×25 mL), and brine (25 mL), dried the organic phase over anhydrous MgSO4, filtered, and concentrated by rotary evaporation to an off-white solid (72 mg). Purified by flash chromatography (silica gel, Alltech Extract-Clean 10 g column, gradient of 6% to 8% MeOH/CH2Cl2) to afford the title compound as an off-white solid (49 mg, 65%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.82 (d, J=6.72 Hz, 6H), 0.86 (d, J=6.72 Hz, 6H), 1.29 (s, 9H), 1.79-2.01 (m, 5H), 2.03-2.22 (m, 4H), 3.53 (s, 6H), 3.70-3.86 (m, 4H), 4.04 (t, J=8.35 Hz, 2H), 5.04 (dd, J=6.67, 3.20 Hz, 2H), 7.23-7.43 (m, 8H), 7.48-7.60 (m, 4H), 7.61-7.73 (m, 4H), 11.77-12.21 (m, 2H); MS (ESI+) m/z 939 (M+H)+.

Workup

  1. customIn an oven-dried 5-mL round bottom flask purged with nitrogen
  2. additionDiluted
  3. washwashed with sat'd aq NaHCO3 (25 mL), H2O (3×25 mL), and brine (25 mL)
  4. dry with materialdried the organic phase over anhydrous MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated by rotary evaporation to an off-white solid (72 mg)
  7. customPurified by flash chromatography (silica gel, Alltech Extract-Clean 10 g column, gradient of 6% to 8% MeOH/CH2Cl2)

Sources & evidence

ORD record
ord-7e14b724413e401182c1a20ccdcce07c
Source dataset
uspto-grants-2015_04
Patent number
US09006387B2

Reaction notes

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