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

HRID 45615

반응식

HRID 45615 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[CH:44]([NH:50][C@H:51](C(O)=O)[CH2:52][CH:53]([CH3:55])[CH3:54])[C:45]([N:47]([CH3:49])[CH3:48])=[O:46]>O1CCCC1.C1(C)C=CC=CC=1>[F:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[C@@H:44]([N:50]1[C@H:51]([CH2:52][CH:53]([CH3:55])[CH3:54])[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]([N:47]([CH3:48])[CH3:49])=[O:46]

참가 물질

7

반응물 4

HCID 7917Isopropyl chloroformateHCID 79724-MethylmorpholineHCID 11208543(R)-2-((tert-Butoxycarbonyl)amino)-2-(2,3-dihydro-1H-inden-2-yl)acetic acidHCID 68842051N-[1-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucine

생성물 1

HCID 11465834(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide수율 27.3%

시약·촉매·용매 2

HCID 1140Toluene용매HCID 8028Tetrahydrofuran용매2회

실험 절차

To a solution of (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid (84 mg) in dry tetrahydrofuran (6 ml) at −20° C. under a nitrogen atmosphere was added N-methylmorpholine (32 l) and a solution of isopropylchloroformate in toluene (1.0M, 290 l). After 10 minutes, a solution of N-[1-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucine (95 mg) in tetrahydrofuran (10 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 (5 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 dissolved in dioxan (5 ml) and to this was added triethylamine (0.5 ml). After 1 hour, the solvent was removed and the residue was applied to an SPE (10 g, silica). The product was eluted using methanol. A second SPE was used to further purify the material (2 g, silica) using an ethyl acetate:methanol gradient (20:1 to 1:1) to afford (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide (38 mg).

후처리

  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 (5 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. dissolutionthe residue was dissolved in dioxan (5 ml)
  9. additionto this was added triethylamine (0.5 ml)
  10. waitAfter 1 hour
  11. customthe solvent was removed
  12. washThe product was eluted
  13. customto further purify the material (2 g, silica)

출처 및 근거

ORD 기록
ord-c86df1da780f41018180a81996c1a2be
출처 데이터셋
uspto-grants-2013_09
특허 번호
US08541579B2

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