1,2-Dichloroethane → 1-(2-(4-tert-butyloxycarbonylphenyl)-2-hydroxy-2-phenylethanoyl)-N-(2-tert-butyloxycarbonylaminomethyl-5-chlorobenzyl)-L-prolinamide

HRID 1058295Notes

Reaction equation

HRID 1058295 reaction equation
[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](O)=[O:16])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([O:29][C:30]([NH:32][CH2:33][C:34]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:35]=1[CH2:36][NH:37][C:38](=[O:44])[C@@H:39]1[CH2:43][CH2:42][CH2:41][NH:40]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C1C=C2N=NN(O)C2=CC=1.O.C(Cl)CCl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:24])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:15]([N:40]2[CH2:41][CH2:42][CH2:43][C@H:39]2[C:38]([NH:37][CH2:36][C:35]2[CH:45]=[C:46]([Cl:49])[CH:47]=[CH:48][C:34]=2[CH2:33][NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:31])=[O:44])=[O:16])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 81531DiisopropylethylamineHCID 27960291-Hydroxybenzotriazole hydrateHCID 11428605L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amideHCID 69939119(4-Tert-butoxycarbonylphenyl)(hydroxy)phenylacetic acid

Product 1

HCID 699392581-(2-(4-tert-butyloxycarbonylphenyl)-2-hydroxy-2-phenylethanoyl)-N-(2-tert-butyloxycarbonylaminomethyl-5-chlorobenzyl)-L-prolinamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of (4-tert-butoxycarbonylphenyl)(hydroxy)phenylacetic acid from the previous step (0.030 g, 0.09 mmol, HPLC RT=2.53 min), L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide (0.037 g, 0.1 mmol) and HOBT hydrate (0.015 g, 0.1 mmol) in DMF (1 mL) was added EDC (0.021 g, 0.1 mmol). Diisopropylethylamine was then added in portions (˜0.06 mL total) to bring the pH of the solution to 6-7 as measured on wetted E. Merck pH indicator strips. The mixture was stirred at ambient temperature for 2 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 (40 mL) and saturated aqueous NaHCO3 (10 mL). The EtOAc layer was separated, dried over anhydrous MgSO4, and filtered. The filtrate solvent was removed under reduced pressure and the oil residue was purified by preparative on a Waters PrepPak using 10-100% CH3CN in H2O with 0.1% TFA as eluant over 60 min. Product-containing fractions were combined and the acetonitrile was removed under reduced pressure. The water layer 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-(2-(4-tert-butyloxycarbonylphenyl)-2-hydroxy-2-phenylethanoyl)-N-(2-tert-butyloxycarbonylaminomethyl-5-chlorobenzyl)-L-prolinamide as a white solid. (0.030 g, 46%; HPLC RT=3.25 min, method B; LC-MS M+H=678).

Workup

  1. customconsumption of the proline starting material
  2. customThe DMF was removed under reduced pressure
  3. customthe residue was partitioned between EtOAc (40 mL) and saturated aqueous NaHCO3 (10 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 oil residue was purified by preparative on a Waters PrepPak
  9. customover 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-b11a3320f05844d6b590b844ba74a199
Source dataset
uspto-grants-2003_02
Patent number
US06515011B2

Reaction notes

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