tert-Butyl (3R)-3-(hydroxymethyl)piperazine-1-carboxylate → tert-Butyl (3S,9aR)-3-[(3S)-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl]hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate

HRID 1501949

Reaktionsgleichung

Reaktionsgleichung von HRID 1501949
[CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C@H:12]3[O:17][CH2:16][C@@H:15]4[CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][N:14]4[CH2:13]3)[CH:9]=2)[C:4](=[O:29])[O:3]1.[CH3:30][C@@H:31]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C@@H:41]3[O:46][CH2:45][C@@H:44]4[CH2:47][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49][CH2:50][N:43]4[CH2:42]3)[CH:38]=2)[C:33](=[O:58])[O:32]1.BrC1C=C2C(=CC=1)C(=O)O[C@@H](C)C2.OC[C@@H]1NCCN(C(OC(C)(C)C)=O)C1>>[CH3:1][C@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C@@H:12]3[O:17][CH2:16][C@H:15]4[CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][N:14]4[CH2:13]3)[CH:9]=2)[C:4](=[O:29])[O:3]1.[CH3:30][C@H:31]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C@H:41]3[O:46][CH2:45][C@H:44]4[CH2:47][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49][CH2:50][N:43]4[CH2:42]3)[CH:38]=2)[C:33](=[O:58])[O:32]1

Komponenten

6

Edukt 4

HCID 24820286tert-Butyl (3R)-3-(hydroxymethyl)piperazine-1-carboxylateHCID 67517728(3S)-6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-oneHCID 71273516tert-Butyl (3R,9aS)-3-[(3R)-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl]hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylateHCID 71273517tert-Butyl (3S,9aS)-3-[(3R)-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl]hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate

Produkt 2

HCID 86727031tert-Butyl (3S,9aR)-3-[(3S)-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl]hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylateHCID 86727032tert-Butyl (3R,9aR)-3-[(3S)-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl]hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate

Versuchsvorschrift

Intermediates 8E and 8F were prepared in a similar manner as Intermediates 8A and 8B except (3S)-6-Bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one and tert-butyl (3R)-3-(hydroxymethyl)piperazine-1-carboxylate were used as the starting materials. The cis/trans mixture was purified via MPLC (20-65% EtOAc/Hex). The faster eluting diastereomer was the trans isomer: 8E: 1H NMR (500 MHz; CDCl3): 8.07 (d, J=8.2 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.27 (s, 1H), 4.71 (dd, J=2.0, 10.7 Hz, 1H), 4.68 (m, 1H), 4.0 (bs, 2H), 3.97 (dd, J=3.1, 11.1 Hz, 2H), 3.48 (t, J=10.8 Hz, 1H), 2.99 (m, 4H), 2.74 (d, J=10.5 Hz, 1H), 2.2 (m, 3H), 1.53 (d, J=6.4 Hz, 3H), 1.49 (s, 9H). (M+1)+403.8F: 1H NMR (500 MHz; CDCl3): 8.09 (d, J=8.9 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.39 (s, 1H), 4.81 (t, J=3.6 Hz, 1H), 4.69 (m, 1H), 3.62 (dd, J=3.0, 11.5 Hz, 1H), 3.42 (m, 1H), 3.24 (dd, J=3.6, 12.1 Hz, 1H), 2.97 (m, 4H), 2.76 (m, 3H), 2.50 (m, 2H), 2.28 (m, 1H), 1.54 (d, J=6.2 Hz, 3H), 1.47 (s, 9H). (M+1)+403.

Aufarbeitung

  1. customThe cis/trans mixture was purified via MPLC (20-65% EtOAc/Hex)
  2. washThe faster eluting diastereomer

Quellen und Nachweise

ORD-Eintrag
ord-585fe8a0a00946fd937301782079f090
Quelldatensatz
uspto-grants-2015_12
Patentnummer
US09206199B2

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