Isopropyl chloroformate → (2R)-2-(benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide

HRID 383977Notes

Reaction equation

HRID 383977 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.[O:36]1[C:40]2[CH:41]=[CH:42][C:43]([CH:45]([NH:51][C@H:52](C(O)=O)[CH2:53][CH:54]([CH3:56])[CH3:55])[C:46]([N:48]([CH3:50])[CH3:49])=[O:47])=[CH:44][C:39]=2[CH:38]=[CH:37]1>O1CCCC1.C1(C)C=CC=CC=1.CN(C)C=O>[O:36]1[C:40]2[CH:41]=[CH:42][C:43]([C@@H:45]([N:51]3[C@H:52]([CH2:53][CH:54]([CH3:56])[CH3:55])[C:6](=[O:7])[NH:8][C@H:9]([CH:13]4[CH2:14][C:15]5[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH2:21]4)[C:10]3=[O:12])[C:46]([N:48]([CH3:49])[CH3:50])=[O:47])=[CH:44][C:39]=2[CH:38]=[CH:37]1

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 68847309N-[1-(benzofuran-5-yl)-2-(dimethylamino)-2-oxoethyl]-L-leucine

Product 1

HCID 11477318(2R)-2-(benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamideYield 7.3%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid (419 mg) in dry tetrahydrofuran (5 ml) at −20° C. under a nitrogen atmosphere was added N-methylmorpholine (158 μl) and a solution of isopropylchloroformate in toluene (1.0M, 1.44 ml). After 10 minutes, a solution of N-[1-(benzofuran-5-yl)-2-(dimethylamino)-2-oxoethyl]-L-leucine (478 mg) in dimethylformamide (5 ml) was added and the reaction was allowed to warm to room temperature. After 20 hours, the solvent was removed in vacuo and the residue was dissolved in 4N hydrochloric acid in dioxan (4 ml). After 4 hours methanol (13 ml) was added and the reaction was left to stand for a further 18 hours. The solvent was then removed in vacuo and the residue was separated between dichloromethane and saturated sodium bicarbonate solution. The organic phase was evaporated in vacuo and the residue was applied to an SPE (10 g, silica). The product was eluted using an ethyl acetate: methanol gradient (3:1 to 1:3) to afford (2R)-2-(benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide (51 mg).

Workup

  1. waitAfter 20 hours
  2. customthe solvent was removed in vacuo
  3. dissolutionthe residue was dissolved in 4N hydrochloric acid in dioxan (4 ml)
  4. additionAfter 4 hours methanol (13 ml) was added
  5. waitthe reaction was left
  6. waitto stand for a further 18 hours
  7. customThe solvent was then removed in vacuo
  8. customthe residue was separated between dichloromethane and saturated sodium bicarbonate solution
  9. customThe organic phase was evaporated in vacuo
  10. washThe product was eluted

Sources & evidence

ORD record
ord-eabaa5492a0842818f24c94d368447e6
Source dataset
uspto-grants-2013_02
Patent number
US08367673B2

Reaction notes

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