Hydrochloric Acid → 2-(trimethylsilyl)ethyl N-[(allyloxy)carbonyl]-L-norleucyl-(4R)-4-[(2-phenyl-6-vinylquinolin-4-yl)oxy]-L-prolinate

HRID 1360095Notes

Reaction equation

HRID 1360095 reaction equation
[C:1]1([C:7]2[CH:16]=[C:15]([O:17][C@H:18]3[CH2:22][N:21](C(OC(C)(C)C)=O)[C@H:20]([C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])[CH2:19]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH:39]=[CH2:40])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1.[CH2:48]([O:51][C:52]([NH:54][C@H:55]([C:60](O)=[O:61])[CH2:56][CH2:57][CH2:58][CH3:59])=[O:53])[CH:49]=[CH2:50].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH2:48]([O:51][C:52]([NH:54][C@H:55]([C:60]([N:21]1[CH2:22][C@H:18]([O:17][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH:39]=[CH2:40])[CH:13]=3)[N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:16]=2)[CH2:19][C@H:20]1[C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])=[O:61])[CH2:56][CH2:57][CH2:58][CH3:59])=[O:53])[CH:49]=[CH2:50]

Participants

7

Reactant 6

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 81531DiisopropylethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 51340333(2S)-2-{[(prop-2-en-1-yloxy)carbonyl]amino}hexanoic acidHCID 576171271-tert-butyl 2-[2-(trimethylsilyl)ethyl] (2S,4R)-4-[(2-phenyl-6-vinylquinolin-4-yl)oxy]pyrrolidine-1,2-dicarboxylate

Product 1

HCID 576170282-(trimethylsilyl)ethyl N-[(allyloxy)carbonyl]-L-norleucyl-(4R)-4-[(2-phenyl-6-vinylquinolin-4-yl)oxy]-L-prolinateYield 95%

Procedure

To a flask containing 1-tert-butyl 2-[2-(trimethylsilyl)ethyl] (2S,4R)-4-[(2-phenyl-6-vinylquinolin-4-yl)oxy]pyrrolidine-1,2-dicarboxylate 5 (45 mg, 0.08 mmol) was added a 4 M solution of HCl in dioxane (1.4 mL, 5.6 mmol). After 1 h, LC-MS analysis indicated complete consumption of the starting material (5) and formation of the desired -Boc product. The volatile components were then removed in vacuo, and the crude material was taken up in DMF (1 mL). To this mixture was added alloc-Nle-OH (4) (26 mg, 0.12 mmol), DIPEA (0.144 mL, 0.8 mmol), and TBTU (39 mg, 0.12 mmol). After stirring at RT for 30 min, complete consumption of the amine was evidenced via LC-MS. The reaction mixture was then worked-up with 1N HCl and EtOAc. The organic layer was washed with brine and dried over MgSO4. The solvent was then removed in vacuo and the crude product was purified on silica (10-50% EtOAc/hexanes) to yield 50 mg (95% yield) of 2-(trimethylsilyl)ethyl N-[(allyloxy)carbonyl]-L-norleucyl-(4R)-4-[(2-phenyl-6-vinylquinolin-4-yl)oxy]-L-prolinate 6. 1H NMR (500 MHz, CDCl3) ppm: mixture of amide rotamers: 8.07 (m, 3H), 7.97 (br s, 1H), 7.88 (m, 1H), 7.54-7.47 (m, 3H), 7.07 (s, 1H), 6.92 (dd, J=17.5 Hz, 10.5 Hz, 1H), 5.90 (d, J=17.5 Hz, 1H), 5.83 (m, 1H), 5.43-5.63 (m, 3H), 5.25-5.13 (m, 2H), 4.79 (app t, J=8 Hz, 1H), 4.65-4.37 (m, 4H), 4.26 (m, 2H), 4.10 and 4.08 (2 d, J=4.0 Hz and 4.5 Hz, 1H), 2.78 (m, 1H), 2.42 (m, 1H), 1.83 (m, 1H), 1.63 (m, 1H), 1.44-1.33 (m, 4H), 1.05-0.98 (m, 2H), 0.92 (m, 3H), 0.05 (s, 9H). LRMS (CI, [M+H]) Calc'd=658.4. Found=658.4. HRMS (APCI, [M+H]+) Calc'd for C37H48N3O6Si: 658.3307. found: 658.3348.

Workup

  1. customconsumption of the starting material (5) and formation of the desired -Boc product
  2. customThe volatile components were then removed in vacuo
  3. customcomplete consumption of the amine
  4. washThe organic layer was washed with brine
  5. dry with materialdried over MgSO4
  6. customThe solvent was then removed in vacuo
  7. customthe crude product was purified on silica (10-50% EtOAc/hexanes)

Sources & evidence

ORD record
ord-a9ed8cf7488e44dc8fbea3cafedb7570
Source dataset
uspto-grants-2011_02
Patent number
US07879797B2

Reaction notes

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