Isopropyl chloroformate → (2R)-2-(2,4-difluorophenyl)-2-[(2R,5R)-5-(2,3-dihydro-1H-inden-2-yl)-2-(2-methylpropyl)-3,6-dioxopiperazin-1-yl]-N-propan-2-ylacetamide

HRID 45611

Reaction equation

HRID 45611 reaction equation
C(O[C:6]([NH:8][C@H:9]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)[C:10]([OH:12])=O)=[O:7])(C)(C)C.CN1CCOCC1.C(OC(Cl)=O)(C)C.[F:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[C@@H:44]([NH:51][C@H:52](C(O)=O)[CH2:53][CH:54]([CH3:56])[CH3:55])[C:45]([NH:47][CH:48]([CH3:50])[CH3:49])=[O:46]>O1CCCC1.C1(C)C=CC=CC=1.CN(C)C=O.O1CCCC1>[F:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[C@@H:44]([N:51]1[C@H:52]([CH2:53][CH:54]([CH3:56])[CH3:55])[C:6](=[O:7])[NH:8][C@H:9]([CH:13]2[CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:21]2)[C:10]1=[O:12])[C:45]([NH:47][CH:48]([CH3:49])[CH3:50])=[O:46]

Participants

8

Reactant 4

HCID 7917Isopropyl chloroformateHCID 79724-MethylmorpholineHCID 11208543(R)-2-((tert-Butoxycarbonyl)amino)-2-(2,3-dihydro-1H-inden-2-yl)acetic acidHCID 57439046N-[(1R)-1-(2,4-difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-L-leucine

Product 1

HCID 6918854(2R)-2-(2,4-difluorophenyl)-2-[(2R,5R)-5-(2,3-dihydro-1H-inden-2-yl)-2-(2-methylpropyl)-3,6-dioxopiperazin-1-yl]-N-propan-2-ylacetamide

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolventHCID 21974620tetrahydrofuran N,N-dimethylformamideSolvent

Procedure

To a solution of (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid (291 mg) in dry tetrahydrofuran (5 ml) under a nitrogen atmosphere at −20° C. was added N-methylmorpholine (101 mg) and a solution of isopropylchloroformate in toluene (1.0M, 1 ml). After 10 minutes, a solution of N-[(1R)-1-(2,4-difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-L-leucine (342 mg) in N,N-dimethylformamide/tetrahydrofuran (5 ml/10 ml) was added and the resultant mixture was stirred at room temperature for 4 hours. The solvent was then removed in vacuo and the residue was treated with 4N hydrochloric acid in dioxane (2 ml). After 4 hours, methanol (5 ml) was added to the reaction mixture and this was left to stand for 18 hours. The solvent was then removed in vacuo and the residue was purified on an SPE cartridge (50 g, silica) eluting with cyclohexane/ethyl acetate (gradient from 4:1 to neat ethyl acetate), which furnished the two diastereomers as white solids (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide; (0.137 g)

Workup

  1. customThe solvent was then removed in vacuo
  2. additionthe residue was treated with 4N hydrochloric acid in dioxane (2 ml)
  3. waitAfter 4 hours
  4. additionmethanol (5 ml) was added to the reaction mixture
  5. waitthis was left
  6. waitto stand for 18 hours
  7. customThe solvent was then removed in vacuo
  8. customthe residue was purified on an SPE cartridge (50 g, silica)
  9. washeluting with cyclohexane/ethyl acetate (gradient from 4:1 to neat ethyl acetate), which

Sources & evidence

ORD record
ord-b5edaba82e584e0b9feba7c16343465c
Source dataset
uspto-grants-2013_09
Patent number
US08541579B2

Linked notes

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