Dicyclohexylcarbodiimide → (2R)-2-hydroxy-3-(phenylmethoxy)propyl (2S)-2-(6-methoxy(2-naphthyl))propanoate

HRID 1873633Notes

Reaction equation

HRID 1873633 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[CH2:18]([O:25][CH2:26][C@H:27]([OH:30])[CH2:28]O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:28][C@H:27]([OH:30])[CH2:26][O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH:7]=[CH:6]2

Participants

5

Reactant 3

HCID 10868DicyclohexylcarbodiimideHCID 156391NaproxenHCID 2724795(R)-3-(benzyloxy)propane-1,2-diol

Product 1

HCID 86600944(2R)-2-hydroxy-3-(phenylmethoxy)propyl (2S)-2-(6-methoxy(2-naphthyl))propanoate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 3.70 g, 16.1 mmol), (R)-(+)-3-benzyloxy-1,2-propanediol (2.92 g, 19.0 mmol), N,N-dimethylaminopyridine (DMAP, 0.40 g, 3.3 mmol) and 1,3-dicyclohexylcarbodiimide (3.61 g, 17.5 mmol) in CH2Cl2 (120 mL) was stirred at ambient temperature overnight. The byproduct, dicyclohexyl urea, was removed by filtration. The reaction mixture was partitioned between HCl (3N, 50 mL) and CH2Cl2 (50 mL×2). The combined organic extracts were back washed with water, brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was separated by silica gel column chromatography eluting with EtOAc:hexane (1:2, Rf=0.23) to give a mixture of the 1- and 2-glycerol ester isomers (88:12, 3.87 g). 1H NMR (300 MHz, CDCl3) δ 7.69-7.64 (m, 3H), 7.40-7.03 (m, 8H), 5.34 (s, 2H), 4.17-4.14 (m, 2H), 3.88 (s, 3H), 3.9-3.85 (m, 2H), 3.33-3.28 (m, 2H), 2.45 (br. d, 1H), 1.56 (d, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.6, 157.6, 137.6, 135.4, 133.6, 129.6, 129.2, 128.8, 128.3, 127.7, 127.61, 127.55, 127.1, 126.1, 125.9, 119.0, 105.5, 73.3, 70.6, 68.8, 65.5, 62.2, 55.2, 45.3, 18.3. Mass spectrum (API-TIS) m/z 412 (M+NH4)+.

Workup

  1. customThe byproduct, dicyclohexyl urea, was removed by filtration
  2. customThe reaction mixture was partitioned between HCl (3N, 50 mL) and CH2Cl2 (50 mL×2)
  3. washThe combined organic extracts were back washed with water, brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customdried under vacuum
  8. customThe product was separated by silica gel column chromatography
  9. washeluting with EtOAc:hexane (1:2, Rf=0.23)
  10. customto give

Sources & evidence

ORD record
ord-95e1223bd23046d1813233b519d1223d
Source dataset
uspto-grants-2012_11
Patent number
US08304409B2

Reaction notes

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