Synthesis of Morphine

Structure of Morphine

C17H19NO3

Principal investigator	James D. White
Publication year	1999
Synthesis type	Formal
Number of steps	28 (linear)
References	J. Org. Chem. 1999, 64, 7871.

Part 1 of 1

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+

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NaOMe

MeOH

Reflux, 6 h, 68%

See the Stobbe Condensation

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Special reagent

[RhCl(COD)]2, H2

1 atm

MeOH, THF

RT, 10 h, 100%

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Br2

AcOH

RT, 10 min, 92%

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P2O5

MsOH

RT, 10 h, 75%

See the Friedel-Crafts Acylation

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Pd(OH)2, NaHCO3, H2

1 atm

MeOH

RT, 45 min, 99%

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LiOH

H2O, THF

RT, 12 h, 100%

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KH, HCO2Me

THF

RT, 8 h

See the Claisen Condensation

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+

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Et3N

CH2Cl2

RT, 12 h

See the Michael Addition

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NaOH

H2O, THF

RT, 10 h, 70% (3 steps)

See the Aldol Condensation

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CH2N2

Et2O, EtOAc

RT, 90%

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NaHCO3, Br2

CHCl3

0 °C, 90 min, 70%

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DBU

PhH

68 °C, 4 h, 90%

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NaBH4

CH2Cl2, i-PrOH

RT, 12 h, 99%

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Pd/C, NaHCO3, H2

1 atm

MeOH

RT, 24 h, 75%

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CH2(OMe)2, P2O5

CHCl3

RT, 4 h, 86%

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LiOH

H2O, THF

RT, 20 h, 100%

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CH2N2, (COCl)2

Et2O, PhH

RT, 19 h, 63%

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Rh2(CH3CONH)4

CH2Cl2

RT, 60 min, 65%

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NH2OH.HCl, NaOAc

MeOH

RT, 6 h, 90%

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DMAP, Et3N, BsCl

CH2Cl2

RT, 60 min

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AcOH

RT, 60 min, 69% (2 steps)

See the Beckmann Rearrangement

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NaH, MeI

PhH

Reflux, 5 h, 95%

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HBr

H2O, MeCN

RT, 2 h, 95%

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Dess-Martin Periodinane

CHCl3

RT, 60 min, 96%

See the Dess-Martin Oxidation

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PhSeCl, KOt-Bu

t-BuOH, THF

0 °C to RT, 90 min

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NaIO4

H2O, THF

RT, 30 h, 64% (2 steps)

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LiAlH4

THF

Reflux, 6 h, 70%

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Remaining...

91% (1 step)

"See : J. Med. Chem. 1977, 20, 164."

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