Synthesis of Morphine

Structure of Morphine

C17H19NO3

Principal investigator	Marshall D. Gates
Publication year	1952
Synthesis type	Total
Number of steps	27 (linear)
References	J. Am. Chem. Soc. 1952, 74, 1109. J. Am. Chem. Soc. 1950, 72, 228. J. Am. Chem. Soc. 1950, 72, 4839. J. Am. Chem. Soc. 1956, 78, 1380.

Part 1 of 1

intermediate structure

Pyr, BzCl

Dioxane

100 °C, 3 h, 71%

intermediate structure

NaNO2

AcOH, H2O

0 °C, 2 h, 89%

intermediate structure

Pd/C, H2

1 atm

AcOH

RT, 45 min

intermediate structure

FeCl3, HCl

H2O

RT, 88% (2 steps)

intermediate structure

SO2

H2O, MeOH

RT, 30 min, 91%

intermediate structure

K2CO3, Me2SO4, NaHSO3

Acetone

RT, 3 h, 82-86%

See the Williamson Ether Synthesis

intermediate structure

NaHSO3, KOH

H2O, MeOH

RT, 80%

intermediate structure

NaNO2

AcOH, H2O

-10 °C, 25 min, 97%

intermediate structure

Pd/C, H2SO4, H2

1 atm

AcOH

RT, 60 min

intermediate structure

FeCl3, HCl

H2O

RT, 89% (2 steps)

intermediate structure

NCCH2CO2Et, K3Fe(CN)6, Et3N

EtOH, H2O

RT, 11 min, 84%

See the Michael Addition

intermediate structure

KOH

H2O, MeOH

25-30 °C, 4 min, 97%

intermediate structure

1,3-Butadiene

Dioxane

85-87 °C, 72 h, 66%

See the Diels-Alder Reaction

intermediate structure

Cu2Cr2O5, H2

27 atm

EtOH

124-131 °C, 4 h, 50%

intermediate structure

NH2NH2, KOH

Diethylene glycol

155 °C, 60 min, 92%

See the Wolff-Kishner Reduction

intermediate structure

NaH, MeI

PhMe

Reflux, 3.5 h

intermediate structure

LiAlH4

Et2O

Reflux, 48 h, 88% (2 steps)

"The enantiomers were resolved with dibenzoyl-(+)-tartaric acid (72 % yield)."

intermediate structure

H2SO4

H2O

100 °C, 5 d, 28%

intermediate structure

KOH, NH2NH2

Diglyme

221-227 °C, 75 min, 33%

"The yield was 54 % brsm."

intermediate structure

Ph2CO, KOt-Bu

PhH, t-BuOH

Reflux, 2.5 h, 90%

See the Oppenauer Oxidation

intermediate structure

Br2
2,4-Dinitrophenylhydrazine

AcOH

RT to reflux, 24 h, 41%

intermediate structure

HCl

Acetone, H2O

Reflux, 20 min, 60%

intermediate structure

PtO2, H2

1 atm

EtOH

RT, 80%

intermediate structure

Br2 , NaOAc
2,4-Dinitrophenylhydrazine

AcOH

RT, 24 h, 26%

intermediate structure

HCl

Acetone, H2O

Reflux, 20 min, 27%

intermediate structure

LiAlH4

THF

Reflux, 46 h, 37%

intermediate structure

Pyr.HCl

220 °C, 6 min, 34%

intermediate structure

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