Dicyclohexylcarbodiimide → N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-L-alanine, methyl ester

HRID 393053Notes

Reaction equation

HRID 393053 reaction equation
CC(C)(O[C:5]([NH:7][C@H:8]([C:28]([O:30][CH3:31])=[O:29])[CH2:9][NH:10][C:11]([O:13][CH2:14][CH:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])=[O:6])C.C1C2C(COC(NC[C@@H](C(OC)=O)N)=O)C3C(=CC=CC=3)C=2C=CC=1.F[C:59](F)(F)[C:60]([OH:62])=O.ClCCl.[Cl:68][C:69]1[CH:77]=[C:76]([C:78]([NH:80][CH2:81][C:82]2[CH:87]=CC=[C:84](O)[CH:83]=2)=[O:79])[CH:75]=[CH:74][C:70]=1C(O)=O.C1C=NC2N(O)N=NC=2C=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.O>[Cl:68][C:69]1[CH:77]=[C:76]([C:78]([NH:80][CH2:81][C:82]2[CH:83]=[CH:84][CH:59]=[C:60]([OH:62])[CH:87]=2)=[O:79])[CH:75]=[CH:74][C:70]=1[C:5]([NH:7][C@H:8]([C:28]([O:30][CH3:31])=[O:29])[CH2:9][NH:10][C:11]([O:13][CH2:14][CH:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])=[O:6]

Participants

9

Reactant 6

HCID 10868DicyclohexylcarbodiimideHCID 181649HOAtHCID 21863450Trifluoroacetic acid methylene chlorideHCID 226613972-Chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoic acidHCID 59977282(S)-2-tert-butoxycarbonylamino-3-(9H-fluoren-9-ylmethoxycarbonylamino)propionic acid methyl esterHCID 695121003-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-L-alanine, methyl ester

Product 1

HCID 131723024N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-L-alanine, methyl esterYield 62%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

A solution of N-[(1,1-dimethylethoxy)carbonyl]-3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-L-alanine, methyl ester (Example 62; 1.50 g, 3.4 mmol) was converted to crude 3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-L-alanine, methyl ester (1.30 g, 112% of the theoretical amount) by treatment with trifluoroacetic acid/dichloromethane (1:1). A portion of this material (0.50 g) was combined with 2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoic acid (449 mg, 1.5 mmol), HOAT (219 mg, 1.6 mmol) and dicyclohexylcarbodiimide (363 mg, 1.8 mmol) in N,N-dimethylformamide (5 mL) and the reaction mixture was stirred at room temperature over the weekend. Water was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried, filtered, evaporated, and chromatographed (2-10% methanol/dichloromethane) to give N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-L-alanine, methyl ester (0.57 g, 62%) as a white solid.

Workup

  1. extractionthe mixture was extracted three times with ethyl acetate
  2. washThe combined organic layers were washed with water and brine
  3. customdried
  4. filtrationfiltered
  5. customevaporated
  6. customchromatographed (2-10% methanol/dichloromethane)

Sources & evidence

ORD record
ord-0ebe6c892df248b5ac7fc53c286791a3
Source dataset
uspto-grants-2004_10
Patent number
US06803384B2

Reaction notes

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