N-Methylbutylamine → 5-n-Butyl-2-[5-(N-n-butyl-N-methylcarbamoyl)-2-chlorophenyl]-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

HRID 36271Notes

Reaction equation

HRID 36271 reaction equation
[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:46])(=[O:45])[NH:35][C:36](=[O:44])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.[CH3:56][NH:57][CH2:58][CH2:59][CH2:60][CH3:61].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:45])(=[O:46])[NH:35][C:36](=[O:44])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([C:16](=[O:18])[N:57]([CH2:58][CH2:59][CH2:60][CH3:61])[CH3:56])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4]

Participants

7

Reactant 4

HCID 8068N-MethylbutylamineHCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 117651285-n-Butyl-2-(5-carboxy-2-chlorophenyl)-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Product 1

HCID 104852025-n-Butyl-2-[5-(N-n-butyl-N-methylcarbamoyl)-2-chlorophenyl]-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-oneYield 36%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 40 mg (0.0589 mmole) of 5-n-butyl-2-(5-carboxy-2-chlorophenyl)-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step A) and 51.3 μL (38.1 mg, 0.295 mmole) of N,N-diisopropylethylamine in 1 mL of CH2Cl2 and 0.3 μL of DMF was stirred at 0° C. under protection from moisture as 27.9 mL (20.5 mg, 0.236 mmole) of N-methylbutylamine was added, followed by 52.1 mg (0.118 mmole) of BOP reagent. The solution was stirred at 0° C. overnight and then concentrated. The residue was reconcentrated twice from toluene. It was then taken up in CH2Cl2 and washed successively twice with 5% citric acid (aqueous), twice with 5% NaHCO3 (aqueous), and then with brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was flash chromatographed on silica gel (gradient elution with 1-5% MeOH in CH2Cl2) and then further purified by HPLC on a semi-preparative Zorbax C8 reverse phase column (elution with 60:40 acetonitrile-H2O) to give a 36% yield of the title compound as a colorless, glassy solid, mp >90° C. (gradual); mass spectrum (FAB) m/e 748 (M+1)+. By NMR the material appeared to exist as a mixture of amide rotamers in a ratio of approximately 1:1.

Workup

  1. additionwas added
  2. concentrationconcentrated
  3. washwashed successively twice with 5% citric acid (aqueous), twice with 5% NaHCO3 (aqueous)
  4. dry with materialThe organic phase was dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customchromatographed on silica gel (gradient elution with 1-5% MeOH in CH2Cl2)
  8. customfurther purified by HPLC on a semi-preparative Zorbax C8 reverse phase column (elution with 60:40 acetonitrile-H2O)

Sources & evidence

ORD record
ord-18583e5eab2e4e7ab787b72429e7de62
Source dataset
uspto-grants-1995_05
Patent number
US05411980

Reaction notes

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