Triethylamine → 3-[[3,5-bis[(tetrahydro-2H-pyran-2-yl)oxy]benzoyl]amino]-N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine, methyl ester

HRID 393093Notes

Reaction equation

HRID 393093 reaction equation
[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:23]=1)[C:11](ON1C(=O)CCC1=O)=[O:12].Cl.[NH2:32][CH2:33][C@@H:34]([C:57]([O:59][CH3:60])=[O:58])[NH:35][C:36](=[O:56])[C:37]1[C:42]([Cl:43])=[CH:41][C:40]([C:44]([NH:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([OH:54])[CH:49]=2)=[O:45])=[CH:39][C:38]=1[Cl:55].C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:23]=1)[C:11]([NH:32][CH2:33][C@@H:34]([C:57]([O:59][CH3:60])=[O:58])[NH:35][C:36](=[O:56])[C:37]1[C:42]([Cl:43])=[CH:41][C:40]([C:44]([NH:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([OH:54])[CH:49]=2)=[O:45])=[CH:39][C:38]=1[Cl:55])=[O:12]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 8857Ethyl AcetateHCID 226612291-[[3,5-bis[(tetrahydro-2H-pyran-2-yl)oxy]benzoyl]oxy]-2,5-pyrrolidinedioneHCID 1317230303-amino-N-[2,6-dichloro-4-[[[(3-hydroxyphenyi)methyl]amino]carbonyl]benzoyl]-L-alanine, methyl ester hydrochloride

Product 1

HCID 1317230463-[[3,5-bis[(tetrahydro-2H-pyran-2-yl)oxy]benzoyl]amino]-N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine, methyl esterYield 52%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of 1-[[3,5-bis[(tetrahydro-2H-pyran-2-yl)oxy]benzoyl]oxy]-2,5-pyrrolidinedione (2.10 g, 5.0 mmol), 3-amino-N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine, methyl ester hydrochloride (Example 75; 2.00 g, 4.2 mmol), and triethylamine (500 mg, 4.9 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. The solvent was evaporated and ethyl acetate (125 mmol) was added. The solution was washed with 0.2 M HCl (125 mL) and the aqueous wash was back-extracted with ethyl acetate (100 mL). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate and brine (30 mL each), evaporated, and chromatographed (50-100% ethyl acetate/hexanes) to give 3-[[3,5-bis[(tetrahydro-2H-pyran-2-yl)oxy]benzoyl]amino]-N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]-carbonyl]benzoyl]-L-alanine, methyl ester (1.61 g, 52%) as a white foam.

Workup

  1. customThe solvent was evaporated
  2. washThe solution was washed with 0.2 M HCl (125 mL)
  3. washthe aqueous wash
  4. extractionwas back-extracted with ethyl acetate (100 mL)
  5. washThe combined organic layers were washed with saturated aqueous sodium hydrogen carbonate and brine (30 mL each)
  6. customevaporated
  7. customchromatographed (50-100% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-2e6adb6cee564ef9991925b6b3bb710a
Source dataset
uspto-grants-2004_10
Patent number
US06803384B2

Reaction notes

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