Pyridine → (3RS,4RS)-N-[(3-{amino[({[(2-ethyl hexyl)oxy]carbonyl}oxy)imino]methyl}benzyl)oxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide

HRID 450806Notes

Reaction equation

HRID 450806 reaction equation
[NH2:1][C:2](=[N:44][OH:45])[C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=1)[CH2:6][O:7][NH:8][C:9]([CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:12]1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[Cl:40])=[O:10].CN(C=O)C.N1C=CC=CC=1.Cl[C:58]([O:60][CH2:61][CH:62]([CH2:67][CH3:68])[CH2:63][CH2:64][CH2:65][CH3:66])=[O:59]>C(OCC)(=O)C>[NH2:1][C:2](=[N:44][O:45][C:58]([O:60][CH2:61][CH:62]([CH2:67][CH3:68])[CH2:63][CH2:64][CH2:65][CH3:66])=[O:59])[C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=1)[CH2:6][O:7][NH:8][C:9]([CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:12]1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[Cl:40])=[O:10]

Participants

6

Reactant 4

HCID 1049PyridineHCID 6228DimethylformamideHCID 627832-Ethylhexyl chloroformateHCID 72303205(3RS,4RS)-N-({3-[amino(hydroxyimino)methyl]benzyl}oxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide

Product 1

HCID 72303604(3RS,4RS)-N-[(3-{amino[({[(2-ethyl hexyl)oxy]carbonyl}oxy)imino]methyl}benzyl)oxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

To a mixed liquid of 280 mg of (3RS,4RS)—N-({3-[amino(hydroxyimino)methyl]benzyl}oxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 10 ml of DMF were added 0.037 ml of pyridine and subsequently 0.084 ml of 2-ethylhexyl chloroformate under ice-cooling, followed by stirring under ice-cooling for 30 minutes. To the reaction solution was added ethyl acetate, followed by washing with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 305 mg of (3RS,4RS)—N-[(3-{amino[({[(2-ethyl hexyl)oxy]carbonyl}oxy)imino]methyl}benzyl)oxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white amorphous substance. To 290 mg of the present compound was added 6 ml of NMP, followed by stirring at 140° C. for 3 hours. The reaction solution was cooled, and 50 ml of water was then added thereto, followed by stirring. The precipitated solid was collected by filtration. This solid was purified by silica gel column chromatography (eluent: chloroform-methanol), then crystallized with acetonitrile-water, and collected by filtration to obtain 101 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-{[3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl]oxy}-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.

Workup

  1. temperaturecooling
  2. temperaturecooling for 30 minutes
  3. washby washing with water
  4. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  5. customthe solvent was then evaporated under reduced pressure
  6. customThe obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol)

Sources & evidence

ORD record
ord-2da03325d43d49ebaf34c7a31511505a
Source dataset
uspto-grants-2013_07
Patent number
US08486970B2

Reaction notes

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