Acetonitrile → (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-{[3-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl]oxy}-1,2,3,4-tetrahydroisoquinoline-4-carboxamide

HRID 450805Notes

Reaction equation

HRID 450805 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].C(#N)C.[C:49](N1C=CN=C1)(N1C=CN=C1)=[S:50].C1CCN2C(=NCCC2)CC1>C(OCC)(=O)C>[Cl:40][C:34]1[CH:35]=[C:36]([Cl:39])[CH:37]=[CH:38][C:33]=1[CH:12]1[CH:11]([C:9]([NH:8][O:7][CH2:6][C:5]2[CH:41]=[CH:42][CH:43]=[C:3]([C:2]3[NH:1][C:49](=[S:50])[O:45][N:44]=3)[CH:4]=2)=[O:10])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[NH:28][S:29]([CH3:32])(=[O:31])=[O:30]

Participants

6

Reactant 4

HCID 6342AcetonitrileHCID 802641,1'-ThiocarbonyldiimidazoleHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 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 178505004(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-{[3-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl]oxy}-1,2,3,4-tetrahydroisoquinoline-4-carboxamideYield 19.1%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

To a mixed liquid of 300 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 30 ml of acetonitrile were added 132 mg of 1,1′-carbonothioyl bis(1H-imidazole) and 0.27 ml of DBU under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated and then added with 50 ml of water, and 1 M hydrochloric acid was added thereto until the pH reached 4 to 5. After extracting with ethyl acetate, washing with a saturated aqueous sodium chloride solution and drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol). The crude purified product thus obtained was added with ethyl acetate and collected by filtration to obtain 61 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-{[3-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl]oxy}-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white solid.

Workup

  1. temperaturecooling
  2. concentrationThe reaction solution was concentrated
  3. additionadded with 50 ml of water, and 1 M hydrochloric acid
  4. additionwas added
  5. extractionAfter extracting with ethyl acetate
  6. washwashing with a saturated aqueous sodium chloride solution
  7. dry with materialdrying over anhydrous magnesium sulfate
  8. customthe solvent was evaporated
  9. customThe residue was purified by silica gel column chromatography (eluent: chloroform-methanol)
  10. customThe crude purified product
  11. customthus obtained
  12. filtrationcollected by filtration

Sources & evidence

ORD record
ord-77ef933dda9747e2a22a93b809ca3622
Source dataset
uspto-grants-2013_07
Patent number
US08486970B2

Reaction notes

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