tert-Butanol → Tert-butyl 2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxy-3-methoxyphenyl)propanoate

HRID 1805902Notes

Reaction equation

HRID 1805902 reaction equation
[CH3:1][C:2](O)([CH3:4])[CH3:3].[C:6]([O:10][C:11]([NH:13][CH:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1)[C:15]([OH:17])=[O:16])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[C:6]([O:10][C:11]([NH:13][CH:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1)[C:15]([O:17][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:16])=[O:12])([CH3:8])([CH3:9])[CH3:7]

Participants

6

Reactant 4

HCID 6386tert-ButanolHCID 786231,1-Bis(2,2-dimethylpropoxy)-N,N-dimethylmethanamineHCID 516892Sodium BicarbonateHCID 179638622-((tert-Butoxycarbonyl)amino)-3-(4-hydroxy-3-methoxyphenyl)propanoic acid

Product 1

HCID 71204796Tert-butyl 2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxy-3-methoxyphenyl)propanoate

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

t-BuOH (5.17 g, 6.67 mL, 69.8 mmol) was added to a stirred suspension of 2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxy-3-methoxyphenyl)propanoic acid (1.55 g, 4.98 mmol) in dry toluene (25 mL). The mixture was brought to reflux to give a homogeneous solution. N,N-dimethylformamide dineopentyl acetal (3.46 g, 4.17 mL, 15.0 mmol) was added dropwise over 1 h at reflux. After heating at reflux to 3-4 h, the reaction mixture was cooled to room temperature and a saturated solution of NaHCO3 (40 mL) was added. The mixture was extracted with CH2Cl2 (3×40 mL) and the combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 360 mL, gradient to 20% EtOAc in hexanes over 4536 mL) to afford tert-butyl 2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxy-3-methoxyphenyl)propanoate. Rf=0.42 (20% EtOAc/hexanes). LCMS calc.=390.2; found=389.9 (M+Na)+. 1H NMR (500 MHz, CDCl3): δ 6.82 (d, J=7.9 Hz, 1 H); 6.87-6.63 (m, 2 H); 5.54 (s, 1 H); 4.97 (d, J=7.8 Hz, 1 H); 4.40 (q, J=6.7 Hz, 1 H); 3.86 (s, 3 H); 2.98 (d, J=6.0 Hz, 2 H); 1.42 (s, 9 H); 1.41 (s, 9 H).

Workup

  1. temperatureto reflux
  2. customto give a homogeneous solution
  3. temperatureat reflux
  4. temperatureAfter heating
  5. temperatureat reflux to 3-4 h
  6. extractionThe mixture was extracted with CH2Cl2 (3×40 mL)
  7. dry with materialthe combined extracts were dried (Na2SO4)
  8. concentrationconcentrated in vacuo
  9. customto give the crude product
  10. customThis was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 360 mL, gradient to 20% EtOAc in hexanes over 4536 mL)

Sources & evidence

ORD record
ord-3cb527cdac11413ab4cb7479e8407ba7
Source dataset
uspto-grants-2013_01
Patent number
US08354454B2

Reaction notes

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