3-Chlorobenzoic Acid → 3-[(3-chlorobenzoyl)amino]-N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine

HRID 1726806Notes

Reaction equation

HRID 1726806 reaction equation
C(N(C(C)C)CC)(C)C.Cl.[NH2:11][CH2:12][C@@H:13]([C:36](OC)=[O:37])[NH:14][C:15](=[O:35])[C:16]1[C:21]([Cl:22])=[CH:20][C:19]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)=[O:24])=[CH:18][C:17]=1[Cl:34].[Cl:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44](O)=[O:45].CN(C([O:57]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.O.[OH-].[Li+]>CN(C)C=O>[Cl:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44]([NH:11][CH2:12][C@@H:13]([C:36]([OH:57])=[O:37])[NH:14][C:15](=[O:35])[C:16]1[C:21]([Cl:22])=[CH:20][C:19]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)=[O:24])=[CH:18][C:17]=1[Cl:34])=[O:45]

Participants

8

Reactant 6

HCID 4473-Chlorobenzoic AcidHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 168937Lithium hydroxide, monohydrateHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 1317230303-amino-N-[2,6-dichloro-4-[[[(3-hydroxyphenyi)methyl]amino]carbonyl]benzoyl]-L-alanine, methyl ester hydrochloride

Product 1

HCID 599773013-[(3-chlorobenzoyl)amino]-N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanineYield 51.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Diisopropylethylamine (220 mg, 1.7 mmol) was added to a cooled (0° C.) solution of 3-amino-N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine, methyl ester hydrochloride (Example 75; 135 mg, 0.28 mmol), 3-chlorobenzoic acid (53 mg, 0.34 mmol), HBTU (136 mg, 0.36 mmol), and HOBT (49 mg, 0.36 mmol) in N,N-dimethylformamide (2 mL). The solution was allowed to stir at room temperature for 4 days, and then the solvent was evaporated. Ethyl acetate (50 mL) was added, and the solution was washed with 1 M HCl, saturated aqueous sodium hydrogen carbonate, and brine (10 mL each), and evaporated. Tetrahydrofuran/methanol (3:1; 4 mL) was added, followed by 10% aqueous lithium hydroxide monohydrate (1 mL, 2.38 mmol). The solution was stirred at room temperature overnight, then the solvent was evaporated and the residue was partitioned between ethyl acetate (30 mL) and 1 M HCl (10 mL). The ethyl acetate layer was evaporated and the residue was dissolved in methanol (˜1 mL), purified by HPLC, and lyophilized to give 3-[(3-chlorobenzoyl)amino]-N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine (81.1 mg, 51%) as a white solid.

Workup

  1. customthe solvent was evaporated
  2. additionEthyl acetate (50 mL) was added
  3. washthe solution was washed with 1 M HCl, saturated aqueous sodium hydrogen carbonate, and brine (10 mL each)
  4. customevaporated
  5. additionTetrahydrofuran/methanol (3:1; 4 mL) was added
  6. stirringThe solution was stirred at room temperature overnight
  7. customthe solvent was evaporated
  8. customthe residue was partitioned between ethyl acetate (30 mL) and 1 M HCl (10 mL)
  9. customThe ethyl acetate layer was evaporated
  10. dissolutionthe residue was dissolved in methanol (˜1 mL)
  11. custompurified by HPLC

Sources & evidence

ORD record
ord-91bb830d4a4441548d1e942adb66479d
Source dataset
uspto-grants-2009_02
Patent number
US07491741B2

Reaction notes

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