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

HRID 1352051Notes

Reaction equation

HRID 1352051 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-ffc2f84295f1467f97fb03aaaff2255f
Source dataset
uspto-grants-2007_05
Patent number
US07217728B2

Reaction notes

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