Synthesis of Morphine

Structure of Morphine

C17H19NO3

Principal investigatorGilbert Stork
Publication year2009
Synthesis typeFormal
Number of steps 22 (linear)
References
Part 1 of 1
intermediate structure
HO(CH2)3OH, TsOH
PhMe
Reflux, , 85%
intermediate structure
Methyl propynoate, Et3N
THF
-20 to 0 °C, 3.5 h, 89%
intermediate structure
Pd(OAc)2, Ph3P, NaOAc, n-Bu4N+ Cl-
DMF, H2O
125 °C, 4 h, 84%
See the Heck Coupling
intermediate structure
HCl
THF, H2O
0 °C, 90 min, 80%
intermediate structure
Ph3P+CH2OMe Cl-, TMS2NK
THF, CH2Cl2
-30 °C to RT, 15.5 h, 95%
See the Wittig Reaction
intermediate structure
HCl
THF, H2O
RT, 2.5 h, 86%
intermediate structure + intermediate structure
  1. Cp2ZrHCl
  2. AgOTf
  3. TESCl
  4. Imidazole
CH2Cl2
-78 °C to RT, 19.5 h, 95%
intermediate structure
Et3N
Decalin
235-240 °C, 24 h, 55%
"The yield was 70 % brsm. Also isolated was the C2-epimer (14 % yield)."
intermediate structure
LiBHEt3
CH2Cl2
0 °C, 90 min, 86%
"The yield was 90 % brsm."
intermediate structure
Dess-Martin Periodinane
CH2Cl2
0 °C to RT, 3.5 h
intermediate structure
Ph3P+CH2OMe Cl-, TMS2NK
THF, CH2Cl2
-50 °C to RT, 15 h, 74% (2 steps)
See the Wittig Reaction
intermediate structure
n-Bu4N+ F-
THF
-50 °C to RT, 2 h, 88%
intermediate structure
Dess-Martin Periodinane
CH2Cl2
0 °C, 4.5 h, 90%
intermediate structure
Li(s-Bu)3BH
THF
-20 °C to RT, 6 h, 53%
"The yield was 70 % brsm."
intermediate structure
MsCl, Et3N
CH2Cl2
0 °C, 6 h, 74%
"The yield was 90 % brsm."
intermediate structure
HCl
THF, H2O
0 °C, 5 h, 86%
"The yield was 98 % brsm."
intermediate structure
MeNH2.HCl, Et3N, NaBH4, Ti(Oi-Pr)4
MeOH
0 °C to RT, 4 h, 93%
intermediate structure
K2CO3
PhH
75 °C, 24 h, 73%
intermediate structure
ClCO2Me, NaHCO3
CHCl3
Reflux, 17 h, 91%
intermediate structure
SeO2, t-BuOOH
H2O
Reflux, 15 h, 72%
"The yield was 89 % brsm."
intermediate structure
LiAlH4
Et2O
-30 °C to Reflux, 3.5 h, 82%
intermediate structure
Remaining...
91% (1 step)
"See : J. Med. Chem. 1977, 20, 164."
intermediate structure