1,2-Dichloroethane → 1-[4-(Thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane

HRID 380194Notes

Reaction equation

HRID 380194 reaction equation
[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:41][C@H:42]([OH:52])[C@@H:43]([NH2:51])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:41][C@H:42]([OH:52])[C@@H:43]([NH:51][C:11](=[O:13])[C@H:6]([C:7]([CH3:8])([CH3:9])[CH3:10])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1

Participants

6

Reactant 4

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 107191051-[4-(Thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexaneHCID 11263950N-(Methoxycarbonyl)-L-tert-leucine

Product 1

HCID 106517251-[4-(Thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

Under an nitrogen atmosphere, 1.36 g (7.2 mmol) of N-methoxycarbonyl-(L)-tert-leucine (Example 2e), 2.59 g (13.5 mmol) of EDC and 1.22 g (9.0 mmol) of HOBT are dissolved in 20 ml of DMF. After 15 min, 3.79 ml (27 mmol) of TEA are added and then a solution of 2.11 g (4.5 mmol) of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane in 41 ml of DMF is added dropwise. After 3 hours the reaction mixture is concentrated by evaporation. The resulting oil is dissolved in ethyl acetate and a small amount of THF and washed with 2×water, sat. NaHCO3 solution, 2×water and brine. The aqueous phases are extracted with ethyl acetate; the combined organic phases are dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; methylene chloride/THF 5:1) and crystallisation from ethyl acetate/DIPE yield the title compound: HPLC20-100: tRet=16.0; FAB MS (M+H)+=640.

Workup

  1. concentrationAfter 3 hours the reaction mixture is concentrated by evaporation
  2. dissolutionThe resulting oil is dissolved in ethyl acetate
  3. washa small amount of THF and washed with 2×water, sat. NaHCO3 solution, 2×water and brine
  4. extractionThe aqueous phases are extracted with ethyl acetate
  5. dry with materialthe combined organic phases are dried (Na2SO4)
  6. concentrationconcentrated by evaporation
  7. customColumn chromatography (SiO2; methylene chloride/THF 5:1) and crystallisation from ethyl acetate/DIPE

Sources & evidence

ORD record
ord-5b4e1a89be5941889028c352632f2439
Source dataset
uspto-grants-2001_10
Patent number
US06300519B1

Reaction notes

Loading…