1,2-Dichloroethane → HCID 69939812, compound

HRID 1058304Notes

Reaction equation

HRID 1058304 reaction equation
[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:11]=1[CH2:12][NH:13][C:14](=[O:20])[C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([O:30][C:31]([C:33]1[CH:34]=[C:35]([C@H:39]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=2)[C@@H:40]([OH:44])[C:41](O)=[O:42])[CH:36]=[CH:37][CH:38]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C1C=C2N=NN(O)C2=CC=1.O.C(Cl)CCl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:26]([O:30][C:31]([C:33]1[CH:34]=[C:35]([C@H:39]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=2)[C@@H:40]([OH:44])[C:41]([N:16]2[CH2:17][CH2:18][CH2:19][C@H:15]2[C:14]([NH:13][CH2:12][C:11]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:10]=2[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:20])=[O:42])[CH:36]=[CH:37][CH:38]=1)=[O:32])([CH3:29])([CH3:27])[CH3:28]

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 81531DiisopropylethylamineHCID 27960291-Hydroxybenzotriazole hydrateHCID 11428605L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amideHCID 69937561HCID 69937561, compound

Product 1

HCID 69939812HCID 69939812, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide (0.026 g, 0.07 mmol), (2R,3R)-3-[3-(tert-butoxycarbonyl)phenyl]-2-hydroxy-3-pyridin-2-ylpropanoic acid from step 6 (20 mg, 0.058 mmol), and HOBT hydrate (12 mg, 0.087 mmol) in DMF (1 mL) was added EDC (0.017 g, 0.087 mmol). Diisopropylethylamine (0.0122 mL, 0.07 mmol) was added and the mixture was stirred at ambient temperature for 3 days, at which time HPLC analysis indicated complete consumption of the proline starting material. The DMF was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and 10% aqueous Na2CO3 (20 mL). The EtOAc layer was separated, dried over anhydrous MgSO4, and filtered. The filtrate solvent was removed under reduced pressure and the residue was purified by preparative HPLC on a Waters PrepPak using 10% to 100% CH3CN:H2O with 0.1% TFA as eluant over 60 min. The product-containing fractions were combined and the acetonitrile was removed under reduced pressure. The remaining aqueous solution was basicified with saturated aqueous NaHCO3, extracted with 4×20 mL CH2Cl2, dried over Na2SO4 and filtered. The filtrate solvent was removed under reduced pressure to give 1-((2R,3R)-3-(3-tert-butyloxycarbonylphenyl)-3-(2-pyridyl)-2-hydroxypropanoyl)-N-(2-tert-butyloxycarbonylaminomethyl-5-chlorobenzyl)-L-prolinamide an oil (0.018 g, 45%). HPLC RT=2.54 min, method B; LC-MS M+H=693, 695.

Workup

  1. customconsumption of the proline starting material
  2. customThe DMF was removed under reduced pressure
  3. customthe residue was partitioned between EtOAc (50 mL) and 10% aqueous Na2CO3 (20 mL)
  4. customThe EtOAc layer was separated
  5. dry with materialdried over anhydrous MgSO4
  6. filtrationfiltered
  7. customThe filtrate solvent was removed under reduced pressure
  8. customthe residue was purified by preparative HPLC on a Waters PrepPak
  9. waitH2O with 0.1% TFA as eluant over 60 min
  10. customthe acetonitrile was removed under reduced pressure
  11. extractionextracted with 4×20 mL CH2Cl2
  12. dry with materialdried over Na2SO4
  13. filtrationfiltered
  14. customThe filtrate solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-5cb0489b51e443abb8b42e37d3bbe25e
Source dataset
uspto-grants-2003_02
Patent number
US06515011B2

Reaction notes

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