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 2108696노트

반응식

HRID 2108696 반응식
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]

참가 물질

8

반응물 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

생성물 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

시약·촉매·용매 3

HCID 1140Toluene용매HCID 8028Tetrahydrofuran용매HCID 21974620tetrahydrofuran N,N-dimethylformamide용매

실험 절차

To a solution of (2R)-[(tert-butoxycarbonyl)amino](2,3dihydro-1H-inden-2-yl)ethanoic acid (291 mg) in dry tetrahydrofuran (5ml) 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)

후처리

  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

출처 및 근거

ORD 기록
ord-1b4e110db58c4e01a0702228fc6c8afd
출처 데이터셋
uspto-grants-2009_04
특허 번호
US07514437B2

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