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

HRID 1276968Notes

Reaction equation

HRID 1276968 reaction equation
S1C(C2C=CC(CN(NC(OC(C)(C)C)=O)C[C@H](O)[C@@H](N[C:25](=[O:36])[C@H:26]([C:32](C)([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])CC3C=CC=CC=3)=CC=2)=CN=C1.[CH3:46][O:47][C:48]([NH:50][C@H:51]([C:56]([OH:58])=O)[C:52]([CH3:55])([CH3:54])[CH3:53])=[O:49].C(Cl)CCl.C1C=CC2N(O)N=[N:69]C=2C=1.[S:73]1[C:77]([C:78]2[CH:83]=[CH:82][C:81]([CH2:84][N:85](NC(OC(C)(C)C)=O)[CH2:86][C@H:87]([OH:97])[C@@H:88]([NH2:96])[CH2:89][C:90]3[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=3)=[CH:80][CH:79]=2)=[CH:76][N:75]=[CH:74]1>CN(C=O)C>[S:73]1[C:77]([C:78]2[CH:83]=[CH:82][C:81]([CH:84]([NH2:69])[N:85]([C:25](=[O:36])[C@H:26]([CH:32]([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:86][C@H:87]([OH:97])[C@@H:88]([NH:96][C:56](=[O:58])[C@H:51]([C:52]([CH3:53])([CH3:54])[CH3:55])[NH:50][C:48]([O:47][CH3:46])=[O:49])[CH2:89][C:90]3[CH:91]=[CH:92][CH:93]=[CH:94][CH:95]=3)=[CH:80][CH:79]=2)=[CH:76][N:75]=[CH:74]1

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 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-azahexaneHCID 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 867557181-[4-(Thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-N-(N-methoxycarbonyl-(L)-valyl)-amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

1-[4-(Thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-(tertbutoxycarbonyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane 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-13d2695022de411c805c705defe6b3c5
Source dataset
uspto-grants-2000_12
Patent number
US06166004

Reaction notes

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