Dimethylamine, hydrochloride → tert-butyl ((3S,7S,8R,9S)-7-benzyl-8-(3-(dimethylamino)-3-oxopropoxy)-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate

HRID 75750Notes

Reaction equation

HRID 75750 reaction equation
[CH2:1]([C@H:8]1[CH2:16][O:15][CH2:14][C@H:13]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12](=[O:25])[O:11][C@@H:10]([CH3:26])[C@@H:9]1[O:27][CH2:28][CH2:29][C:30]([OH:32])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[CH2:34][N:35](C(C)C)[CH:36](C)C.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C.Cl.CNC>CN(C)C=O.CCOC(C)=O>[CH2:1]([C@@H:8]1[C@@H:9]([O:27][CH2:28][CH2:29][C:30]([N:35]([CH3:36])[CH3:34])=[O:32])[C@H:10]([CH3:26])[O:11][C:12](=[O:25])[C@@H:13]([NH:17][C:18](=[O:19])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][O:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

8

Reactant 5

HCID 10473Dimethylamine, hydrochlorideHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 81531DiisopropylethylamineHCID 867012393-(((3S,6S,7R,8S)-8-benzyl-3-((tert-butoxycarbonyl)amino)-6-methyl-4-oxo-1,5-dioxonan-7-yl)oxy)propanoic acidHCID 178418300HCID 178418300, compound

Product 1

HCID 86701243tert-butyl ((3S,7S,8R,9S)-7-benzyl-8-(3-(dimethylamino)-3-oxopropoxy)-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamateYield 78.5%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent2×

Procedure

A solution of 3-(((3S,6S,7R,8S)-8-benzyl-3-((tert-butoxycarbonyl)amino)-6-methyl-4-oxo-1,5-dioxonan-7-yl)oxy)propanoic acid (250 mg, 0.554 mmol, 1.00 equiv), Hünig's base (0.484 mL, 2.77 mmol, 5.00 equiv), hydroxybenzotriazole (HOBT; 85 mg, 0.55 mmol, 1.00 equiv), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC; 159 mg, 0.831 mmol, 1.50 equiv) in N,N-dimethylformamide (DMF; 5.5 mL, 0.1 M) were stirred at room temperature for 10 min, and then dimethylamine hydrochloride (54 mg, 0.66 mmol, 1.2 equiv) was added. The resulting solution was stirred at room temperature for 3 days (d). The reaction was diluted with EtOAc (20 mL) and washed with ½ sat'd NaCl (20 mL), and the phases separated. The aqueous phase was extracted with EtOAc (10 mL), and the combined organic extracts were dried over MgSO4, filtered, and concentrated to provide a yellow oil. The product was purified by automated silica gel column chromatography (5-35% acetone in hexanes) to provide an oily solid that by TLC still had a large amount of DMF. The oily solid was taken up in 20 mL EtOAc and washed with ½ sat'd NaCl (2×10 mL), dried over MgSO4, filtered and concentrated to provide tert-butyl ((3S,7S,8R,9S)-7-benzyl-8-(3-(dimethylamino)-3-oxopropoxy)-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate (208 mg, 78%) as an off-white solid: mp 142-143° C.; 1H NMR (400 MHz, CDCl3) δ 7.32-7.27 (m, 2H), 7.23-7.14 (m, 3H), 5.12 (d, J=7.6 Hz, 1H), 4.94 (dq, J=9.2, 6.3 Hz, 1H), 4.60 (d, J=7.4 Hz, 1H), 4.02 (dd, J=15.5, 6.8 Hz, 1H), 3.93-3.81 (m, 2H), 3.49 (d, J=10.8 Hz, 1H), 3.42-3.33 (m, 1H), 3.34-3.25 (m, 1H), 3.21-3.08 (m, 2H), 3.02 (s, 3H), 2.94 (s, 3H), 2.71-2.51 (m, 2H), 2.31 (t, J=12.7 Hz, 1H), 1.92 (s, 1H), 1.50 (d, J=6.4 Hz, 3H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.15, 170.50, 154.97, 139.88, 129.11, 128.42, 126.09, 85.45, 80.09, 77.22, 75.43, 73.11, 72.81, 68.77, 53.07, 47.17, 37.35, 35.37, 35.12, 33.77, 28.26, 18.77; HRMS-ESI (m/z) [M+H]+ calc'd for C25H39N2O7, 480.2784. found, 480.2785.

Workup

  1. washwashed with ½ sat'd NaCl (20 mL)
  2. customthe phases separated
  3. extractionThe aqueous phase was extracted with EtOAc (10 mL)
  4. dry with materialthe combined organic extracts were dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto provide a yellow oil
  8. customThe product was purified by automated silica gel column chromatography (5-35% acetone in hexanes)
  9. customto provide an oily solid that by TLC
  10. washwashed with ½ sat'd NaCl (2×10 mL)
  11. dry with materialdried over MgSO4
  12. filtrationfiltered
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-6fd3f9385edd457a9f1d0a654fc8dcfa
Source dataset
uspto-grants-2014_09
Patent number
US08835462B2

Reaction notes

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