1-Hydroxybenzotriazole → N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[[(1,1-dimethylethoxy)carbonyl]amino]-L-alanine, methyl ester

HRID 1726767Notes

Reaction equation

HRID 1726767 reaction equation
C(N(C(C)C)CC)(C)C.[Cl: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]=[C:16]([Cl:31])[C:12]=1[C:13]([OH:15])=O.Cl.[CH3:33][C:34]([CH3:47])([O:36][C:37]([NH:39][CH2:40][C@@H:41]([C:43]([O:45][CH3:46])=[O:44])[NH2:42])=[O:38])[CH3:35].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[Cl:31][C:16]1[CH:17]=[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:19]=[C:11]([Cl:10])[C:12]=1[C:13]([NH:42][C@H:41]([C:43]([O:45][CH3:46])=[O:44])[CH2:40][NH:39][C:37]([O:36][C:34]([CH3:47])([CH3:35])[CH3:33])=[O:38])=[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 18334328methyl (2S)-2-amino-3-{[(tert-butoxy)carbonyl]amino}propanoate hydrochlorideHCID 226615502,6-Dichloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoic acid

Product 1

HCID 131723029N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[[(1,1-dimethylethoxy)carbonyl]amino]-L-alanine, methyl esterYield 73%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Diisopropylethylamine (14 mL, 80.6 mmol) was added to a cooled (˜0° C.) solution of 2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoic acid (Example 29; 7.44 g, 21.9 mmol), 3-[[(1,1-dimethylethoxy)carbonyl]amino]-L-alanine, methyl ester, hydrochloride (6.15 g, 24.1 mmol), HOBT (3.12 g; 22.8 mmol), and HBTU (8.64 g, 22.8 mmol) in N,N-dimethyl-formamide (200 mL). The mixture was stirred at room temperature for 16 h. The solvent was evaporated and ethyl acetate (200 mL) was added. The solution was washed with 1 M HCl (100 mL) and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate, and brine (200 mL each), dried (MgSO4), filtered, evaporated, and chromatographed (70% ethyl acetate/hexanes) to give N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[[(1,1-dimethylethoxy)carbonyl]amino]-L-alanine, methyl ester (8.64 g, 73%) as a white foam.

Workup

  1. customThe solvent was evaporated
  2. additionethyl acetate (200 mL) was added
  3. washThe solution was washed with 1 M HCl (100 mL)
  4. extractionthe aqueous layer was extracted with ethyl acetate (100 mL)
  5. washThe combined organic layers were washed with saturated aqueous sodium hydrogen carbonate, and brine (200 mL each)
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. customevaporated
  9. customchromatographed (70% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-751eb4c24f18440a8f5915806b4c9c87
Source dataset
uspto-grants-2009_02
Patent number
US07491741B2

Reaction notes

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