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Diisopropylethylamine → 4-Benzyl 1-tert-butyl (2S)-2-{[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl-amino]carbonyl}-1,4-piperazinedicarboxylate

HRID 2079759
ノート
印刷プレビュー

反応式

HRID 2079759 の反応式
[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:13]([C:24]([OH:26])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.[N:43]1(OC(N(C)C)=[N+](C)C)[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2N=N1.O.ON1[C:66]2[CH:67]=CC=[CH:70][C:65]=2N=N1>CN(C=O)C.CCOC(C)=O>[C@H:47]1([NH:43][C:24]([C@@H:13]2[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15][N:14]2[C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[O:26])[C:46]2[C:51](=[CH:70][CH:65]=[CH:66][CH:67]=2)[CH2:50][CH2:49][CH2:48]1
参加物実験手順後処理出典と根拠反応ノート

参加物

7

反応物 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 27960291-Hydroxybenzotriazole hydrateHCID 70106521-(1,1-Dimethylethyl) 4-(phenylmethyl) (2S)-1,2,4-piperazinetricarboxylate

生成物 1

HCID 59440336
4-Benzyl 1-tert-butyl (2S)-2-{[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl-amino]carbonyl}-1,4-piperazinedicarboxylate
収率 87%

試薬・触媒・溶媒 2

HCID 6228Dimethylformamide溶媒HCID 8857Ethyl Acetate溶媒

実験手順

(2S)-4-[(benzyloxy)carbonyl]-1-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid (1, 17.33 g, 47.5 mmol) is dissolved in DMF (800 mL), to which is added diisopropylethylamine (DIEA, 41.5 mL, 0.24 mol). This mixture is stirred at RT for 1.5 h. R-(−)-1,2,3,4-tetrahydro-1-naphthylamine (7.00 g, 47.5 mmol) is added, and stirring continued for a further hour. O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 19.84 g, 52.3 mmol) and 1-hydroxybenzotriazole hydrate (HOBt, 7.07 g, 52.3 mmol) are also added and the entire mixture stirred overnight at RT. The reaction mixture is then diluted with EtOAc (1.2 L) and washed sequentially with 1 M citric acid, brine, sat. NaHCO3, brine, water and brine (1 L of each solution). The EtOAc layer is then dried with Na2SO4, filtered, and the solvent removed under reduced pressure to afford a crude off-white solid (23.34 g). This material is purified by flash chromatography on silica gel (CH2Cl2 as eluent initially, followed by 5% Et2O/CH2Cl2 to elute the desired product). The desired coupled product 6 is isolated as a white foam (20.37 g, 87% yield): 1H NMR δ (CDCl3) 7.27-7.42 (m, 5H), 7.06-7.19 (m, 4H), 6.10 (brs, 1H), 5.11-5.25 (br m, 3H), 4.46-4.75 (br m, 2H), 3.77-4.02 (br m, 2H), 3.00-3.31 (br m, 3H), 2.68-2.84 (m, 2H), 1.97-2.07 (br m, 1H), 1.69-1.84 (br m, 3H), 1.43 (s, 9H). LCMS (APCl+) 494.8 (MH+), 438.5 (MH+-tBu), 394.4 (MH+-BOC).

後処理

  1. stirringstirring
  2. waitcontinued for a further hour
  3. stirringthe entire mixture stirred overnight at RT
  4. washwashed sequentially with 1 M citric acid, brine, sat. NaHCO3, brine, water and brine (1 L of each solution)
  5. dry with materialThe EtOAc layer is then dried with Na2SO4
  6. filtrationfiltered
  7. customthe solvent removed under reduced pressure
  8. customto afford a crude off-white solid (23.34 g)
  9. customThis material is purified by flash chromatography on silica gel (CH2Cl2 as eluent initially
  10. washto elute the desired product)

出典と根拠

ORDレコード
ord-e8ea4aac54304dd8ae5748357824edec
出典データセット
uspto-grants-2011_04
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US07932255B2

反応ノート

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