1-Hydroxybenzotriazole → N-[2-bromo-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine methyl ester

HRID 1352064Notes

Reaction equation

HRID 1352064 reaction equation
C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:56][O:57][C:58](=[O:70])[C@H:59]([CH2:61][NH:62][C:63]([C:65]1[S:66][CH:67]=[CH:68][CH:69]=1)=[O:64])[NH2:60].C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[Br:10][C:11]1[CH:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:21])[CH:17]=[CH:16][C:12]=1[C:13]([NH:60][C@H:59]([C:58]([O:57][CH3:56])=[O:70])[CH2:61][NH:62][C:63]([C:65]1[S:66][CH:67]=[CH:68][CH:69]=1)=[O:64])=[O:15]

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 226613232-Bromo-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoic acidHCID 688207093-(thiophene-2-carbonyl)amino-L-alanine methyl ester hydrochloride

Product 1

HCID 59977283N-[2-bromo-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine methyl esterYield 83%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Diisopropylethylamine (305 μL, 1.71 mmol) was added dropwise to a solution of 2-bromo-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoic acid (Example 47; 150 mg, 0.428 mmol), HBTU (179 mg, 0.471 mmol), 3-(thiophene-2-carbonyl)amino-L-alanine methyl ester HCl salt (Example 301; 125 mg, 0.471 mmol), and HOBT (64 mg, 0.471 mmol) in N,N-dimethylformamide (6.5 mL) at 25° C. The solution was stirred for 6 h. The solvent was concentrated under vacuum to remove most of the N,N-dimethylformamide. The residue was diluted with ethyl acetate (60 mL) and washed with 1 N HCl (10 mL), water (10 mL), saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried (MgSO4), filtered, evaporated and flash chromatographed (silica, 60–75% ethyl acetate in petroleum ether) to give N-[2-bromo-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester (198 mg, 83%) as an off-white foam.

Workup

  1. concentrationThe solvent was concentrated under vacuum
  2. customto remove most of the N,N-dimethylformamide
  3. additionThe residue was diluted with ethyl acetate (60 mL)
  4. washwashed with 1 N HCl (10 mL), water (10 mL), saturated aqueous NaHCO3 (10 mL) and brine (10 mL)
  5. dry with materialThe organic layer was dried (MgSO4)
  6. filtrationfiltered
  7. customevaporated
  8. customflash chromatographed (silica, 60–75% ethyl acetate in petroleum ether)

Sources & evidence

ORD record
ord-f96764128997487598b8fdf02694e7fd
Source dataset
uspto-grants-2007_05
Patent number
US07217728B2

Reaction notes

Loading…