4-Methylmorpholine → tert-butyl (5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H-fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oate

HRID 2282805

反応式

HRID 2282805 の反応式
[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:26])[C@H:19]([C:23](O)=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:27][O:28][C@@H:29]([C@@H:38]([N:43]([CH3:51])[C:44](=[O:50])[C@H:45]([CH:47]([CH3:49])[CH3:48])[NH2:46])[C@@H:39]([CH3:42])[CH2:40][CH3:41])[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1>CC1CCCO1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:26])[C@H:19]([C:23]([NH:46][C@H:45]([C:44]([N:43]([C@@H:38]([C@@H:39]([CH3:42])[CH2:40][CH3:41])[C@H:29]([O:28][CH3:27])[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[CH3:51])=[O:50])[CH:47]([CH3:49])[CH3:48])=[O:24])[CH:20]([CH3:21])[CH3:22])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1

参加物

6

反応物 4

HCID 79724-MethylmorpholineHCID 184502-Chloro-4,6-dimethoxy-1,3,5-triazineHCID 978328(2S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-methylbutanoic acidHCID 10546343(3R,4S,5S)-tert-butyl 4-((S)-2-amino-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoate

生成物 1

HCID 71294595tert-butyl (5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H-fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oate収率 108.4%

試薬・触媒・溶媒 1

HCID 73012-Methyltetrahydrofuran溶媒

実験手順

To a mixture of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N-methyl-L-valine (19.54 g, 55.29 mmol, 1.3 eq.) and #6 (15.25 g, 42.54 mmol, 1 eq.) in 2-methyltetrahydrofuran (152 mL, 0.28 M) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (9.71 g, 55.3 mmol, 1.3 eq.). After 10 minutes, N-methylmorpholine (6.6 mL, 60 mmol, 1.4 eq.) was slowly added, while keeping the internal temp below 25° C. The reaction was stirred for 4 hours and was then quenched by the addition of water (50 mL). After stirring for 15 minutes, the aqueous layer was separated and back-extracted with 2-methyltetrahydrofuran (50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (100 mL), then were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting yellow foam was purified by silica gel chromatography (Gradient: 5% to 35% ethyl acetate in heptane) to give #7 (32 g, 97%). 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ 7.89 (d, J=7.4 Hz, 2H), 7.62 (d, J=7.4 Hz, 2H), 7.41 (br dd, J=7.4, 7.4 Hz, 2H), 7.29-7.34 (m, 2H), 4.52-4.69 (br m, 1H), 3.70-3.82 (br m, 1H), 3.22 and 3.25 (2 br s, total 3H), 2.94 and 2.96 (2 br s, total 3H), 2.78 and 2.81 (2 br s, total 3H), 2.11-2.23 (m, 1H), 1.90-2.10 (m, 2H), 1.68-1.83 (br m, 1H), 1.40 (s, 9H), 1.21-1.33 (br m, 1H).

後処理

  1. customthe internal temp below 25° C
  2. customwas then quenched by the addition of water (50 mL)
  3. stirringAfter stirring for 15 minutes
  4. customthe aqueous layer was separated
  5. extractionback-extracted with 2-methyltetrahydrofuran (50 mL)
  6. washThe combined organic layers were washed with saturated aqueous sodium bicarbonate solution (100 mL)
  7. dry with materialwere dried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe resulting yellow foam was purified by silica gel chromatography (Gradient: 5% to 35% ethyl acetate in heptane)

出典と根拠

ORDレコード
ord-f487c6faaf9a4ccab6a8ab81114569aa
出典データセット
uspto-grants-2015_09
特許番号
US09138486B2

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