4-Methylmorpholine → HCID 67682294, compound

HRID 1751593Notes

Reaction equation

HRID 1751593 reaction equation
[NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]1[NH:7][C:8]([C:11]2[CH:24]=[C:23]3[O:25][CH2:26][C:20]4[C:21]5[C:22]3=[C:13]([CH2:14][O:15][C:16]=5[CH:17]=[C:18]([C:27]3[NH:31][C:30]([C@@H:32]5[CH2:36][CH2:35][CH2:34][N:33]5C(OC(C)(C)C)=O)=[N:29][CH:28]=3)[CH:19]=4)[CH:12]=2)=[CH:9][N:10]=1.N1CCC[C@H]1C1NC(C2C=C3COC4C5=C(C=C(C6NC([C@@H]7CCCN7)=NC=6)C=4)COC(C=2)=C35)=CN=1.[CH3:80][O:81][C:82]([NH:84][C@@H:85]([CH:89]([CH3:91])[CH3:90])[C:86](O)=[O:87])=[O:83].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O>[CH3:90][CH:89]([CH3:91])[C@H:85]([NH:84][C:82](=[O:83])[O:81][CH3:80])[C:86](=[O:87])[N:33]1[CH2:34][CH2:35][CH2:36][C@H:32]1[C:30]1[NH:31][C:27]([C:18]2[CH:19]=[C:20]3[CH2:26][O:25][C:23]4[C:22]5=[C:13]([CH:12]=[C:11]([C:8]6[NH:7][C:6]([C@@H:2]7[CH2:3][CH2:4][CH2:5][NH:1]7)=[N:10][CH:9]=6)[CH:24]=4)[CH2:14][O:15][C:16]([CH:17]=2)=[C:21]35)=[CH:28][N:29]=1

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 10942966(2S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acidHCID 67682516HCID 67682516, compoundHCID 86708785HCID 86708785, compound

Product 1

HCID 67682294HCID 67682294, compoundYield 12%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

The mixture of (S)-tert-butyl 2-(5-(7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate and 2,7-bis(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromene obtained in the previous step was dissolved in dimethylformamide (6 mL). To this solution was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (194 mg, 1.11 mmol), HATU (309 mg, 0.81 mmol), and N-methylmorpholine (0.24 mL, 2.2 mmol). The reaction was stirred at room temperature for thirty minutes, and then quenched by the addition of formic acid (0.05 mL). The reaction was concentrated and the resulting residue was purified by preparative reverse phase HPLC (Gemini, 10 to 45% ACN/H2O+0.1% TFA) to yield methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (59 mg, 12%) as the tris-TFA salt. Also isolated from the reaction were (S)-tert-butyl 2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (124 mg, 23%) and dimethyl (2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(5,10-dihydrochromeno-[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate (50 mg, 8%).

Workup

  1. customobtained in the previous step
  2. customquenched by the addition of formic acid (0.05 mL)
  3. concentrationThe reaction was concentrated
  4. customthe resulting residue was purified by preparative reverse phase HPLC (Gemini, 10 to 45% ACN/H2O+0.1% TFA)

Sources & evidence

ORD record
ord-de1862b674804439ac022b1af3e4f917
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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