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 346953Notes

Reaction equation

HRID 346953 reaction equation
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]

Participants

8

Reactant 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

Product 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 esterYield 79%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 21226206Ethyl acetate hexaneSolvent

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-ddad8440a722408998573110664c12d5
Source dataset
uspto-grants-2007_02
Patent number
US07173004B2

Reaction notes

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