4-Methylmorpholine → HCID 86708813, compound

HRID 1751748Notes

Reaction equation

HRID 1751748 reaction equation
C(OC([N:11]1[C@@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]1[C:17]1[NH:18][C:19]([C:22]2[CH:35]=[C:34]3[O:36][CH2:37][C:31]4[C:32]5[C:33]3=[C:24]([CH2:25][O:26][C:27]=5[CH:28]=[C:29]([C:38]3[NH:42][C:41]([C@@H:43]5[CH2:47][C@H:46]([CH2:48][O:49][CH3:50])[CH2:45][N:44]5[C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[N:40][CH:39]=3)[CH:30]=4)[CH:23]=2)=[CH:20][N:21]=1)=O)C1C=CC=CC=1.[CH3:58][O:59][C:60]([NH:62][C@@H:63]([CH:67]([CH3:69])[CH3:68])[C:64](O)=[O:65])=[O:61].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.CCOC(C)=O.[Pd]>[CH3:58][O:59][C:60]([NH:62][C@@H:63]([CH:67]([CH3:69])[CH3:68])[C:64]([N:11]1[C@@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]1[C:17]1[NH:18][C:19]([C:22]2[CH:35]=[C:34]3[O:36][CH2:37][C:31]4[C:32]5[C:33]3=[C:24]([CH2:25][O:26][C:27]=5[CH:28]=[C:29]([C:38]3[NH:42][C:41]([C@@H:43]5[CH2:47][C@H:46]([CH2:48][O:49][CH3:50])[CH2:45][N:44]5[C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52])=[N:40][CH:39]=3)[CH:30]=4)[CH:23]=2)=[CH:20][N:21]=1)=[O:65])=[O:61]

Participants

8

Reactant 4

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 67682593HCID 67682593, compound

Product 1

HCID 86708813HCID 86708813, compoundYield 58.5%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

(2S,4S)-tert-butyl 2-(5-(7-(2-((2S,5S)-1-(benzyloxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (300 mg, 0.38 mmol) 10 mL ethanol, and 19 mg 10% Pd/C was stirred under an atmosphere of hydrogen (balloon) overnight. Filtration through celite and concentration afforded the crude amine. The crude amine was dissolved in DMF (4 mL) and then (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (66 mg, 0.38 mmol), HATU (160 mg, 0.42 mmol) and N-methylmorpholine (0.084 mL, 0.76 mmol) were added. After 2 h, the reaction was diluted with EtOAc and washed successively with saturated aqueous NaHCO3, 5% LiCl, and brine. The organic phase was dried over Na2SO4, concentrated, and purified by silica gel chromatography (1% to 20% MeOH/EtOAc) to afford (2S,4S)-tert-butyl 2-(5-(7-(2-((2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (177 mg, 58%).

Workup

  1. filtrationFiltration
  2. concentrationthrough celite and concentration
  3. customafforded the crude amine
  4. washwashed successively with saturated aqueous NaHCO3, 5% LiCl, and brine
  5. dry with materialThe organic phase was dried over Na2SO4
  6. concentrationconcentrated
  7. custompurified by silica gel chromatography (1% to 20% MeOH/EtOAc)

Sources & evidence

ORD record
ord-f59dca43eae54f6093e2ff5e11a00cf7
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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