4-Methylmorpholine → 1-{[1-(5-Allyloxy-2-tert-butoxycarbonylamino-pentanoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester

HRID 346953ノート

反応式

HRID 346953 の反応式
Cl.Cl.[CH2:3]([O:5][C:6]([C:8]1([NH:13][C:14]([CH:16]2[CH2:20][CH:19]([O:21][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=4)[CH:25]=[CH:24][N:23]=3)[CH2:18][NH:17]2)=[O:15])[CH2:10][CH:9]1[CH:11]=[CH2:12])=[O:7])[CH3:4].[CH2:34]([O:37][CH2:38][CH2:39][CH2:40][CH:41]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:42](O)=[O:43])[CH:35]=[CH2:36].C(OCCC[C@H](NC(OC(C)(C)C)=O)C(O)=O)C=C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH2:3]([O:5][C:6]([C:8]1([NH:13][C:14]([CH:16]2[CH2:20][CH:19]([O:21][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=4)[CH:25]=[CH:24][N:23]=3)[CH2:18][N:17]2[C:42](=[O:43])[CH:41]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:40][CH2:39][CH2:38][O:37][CH2:34][CH:35]=[CH2:36])=[O:15])[CH2:10][CH:9]1[CH:11]=[CH2:12])=[O:7])[CH3:4]

参加物

8

反応物 5

HCID 79724-MethylmorpholineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 21080138N-Boc-5-(2-propen-1-yloxy)-L-norvalineHCID 210801395-Allyloxy-2-tert-butoxycarbonylamino-pentanoic acidHCID 687486041-{[4-(6-Methoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester dihydrochloride

生成物 1

HCID 687495351-{[1-(5-Allyloxy-2-tert-butoxycarbonylamino-pentanoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester収率 79%

試薬・触媒・溶媒 2

HCID 6228Dimethylformamide溶媒HCID 21226206Ethyl acetate hexane溶媒

実験手順

A solution of 1-{[4-(6-Methoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester dihydrochloride (Example 22)(3.60 g, 7.25 mmol) and 5-allyloxy-2-tert-butoxycarbonylamino-pentanoic acid (the product of step 26E, 1.98 g, 7.25 mmol) in 75 ml of DMF was treated with HATU (3.31 g, 8.7 mmol) and N-methylmorpholine (2.79 ml, 25.4 mmol). The reaction mixture was stirred at rt under N2 for 4 h, and then quenched with pH 4 buffer (biphthalate). The resulting mixture was extracted with EtOAc. The organic phase was washed with sat. aq. NaCl, dried (MgSO4), and concentrated in vacuo to give the crude product. Flash chromatography (silica gel, 10–60% ethyl acetate/hexane) gave 3.91 g (˜79%) of 1-{[1-(5-Allyloxy-2-tert-butoxycarbonylamino-pentanoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester as a yellow collapsed foam: 1H NMR (500 MHz, METHANOL-D4) δ 1.05–1.16 (m, 1H), 1.32 (s, 9H), 1.37–1.50 (m, 3H), 1.51–1.67 (m, 3H), 1.68–1.84 (m, 2H), 2.17–2.30 (m, 1H), 2.32–2.50 (m, 1H), 2.58–2.73 (m, 1H), 2.80 (s, 1H), 3.33–3.52 (m, 2H), 3.86–3.95 (m, 5H), 4.00–4.06 (m, 1H), 4.07–4.22 (m, 3H), 4.23–4.38 (m, 1H), 4.58–4.67 (m, 1H), 5.04–5.17 (m, 2H), 5.18–5.34 (m, 2H), 5.65–5.94 (m, 3H), 7.07–7.28 (m, 3H), 7.82–7.92 (m, 1H), 7.96–8.13 (m, 1H). LC-MS (Method B, retention time: 1.75 min), MS m/z 681 (M++1).

後処理

  1. customquenched with pH 4 buffer (biphthalate)
  2. extractionThe resulting mixture was extracted with EtOAc
  3. washThe organic phase was washed with sat. aq. NaCl
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated in vacuo
  6. customto give the crude product

出典と根拠

ORDレコード
ord-ddad8440a722408998573110664c12d5
出典データセット
uspto-grants-2007_02
特許番号
US07173004B2

反応ノート

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