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

反応式

HRID 45611 の反応式
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]

参加物

8

反応物 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

生成物 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

試薬・触媒・溶媒 3

HCID 1140Toluene溶媒HCID 8028Tetrahydrofuran溶媒HCID 21974620tetrahydrofuran N,N-dimethylformamide溶媒

実験手順

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)

後処理

  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

出典と根拠

ORDレコード
ord-b5edaba82e584e0b9feba7c16343465c
出典データセット
uspto-grants-2013_09
特許番号
US08541579B2

関連ノート

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