6
774
J . Org. Chem. 1996, 61, 6774
Dir ect a n d Sim p le O-Dem eth yla tion of
Th eba in e to Or ip a vin e
of 2, while the steric bulk would prevent close approach
to C-5 and hence cleavage of the labile ether bridge. We
found that this was indeed the case, with the greatest
yields (23%) of oripavine being obtained with 1 M
L-Selectride in THF at reflux for 30 min. Longer reaction
times gave rise to products of further reaction, notably
those due to 6-O-demethylation. Although the yield was
low, 31% of unreacted thebaine could be recovered.
Further study of the reaction conditions led to the
discovery that prolonged stirring (14 days) at room
temperature gave a 35% yield of oripavine but lower
recovery (5%) of thebaine.12
†
Andrew Coop, J ohn W. Lewis, and Kenner C. Rice*
Laboratory of Medicinal Chemistry, National Institute of
Diabetes, Digestive and Kidney Diseases, Building 8,
Room B1-23, Bethesda, Maryland 20892-0815, and
School of Chemistry, University of Bristol, Cantock’s Close,
Bristol BS8 1TS, U.K.
Received August 2, 1996
Oripavine (1) is a potentially valuable starting material
The ease of this transformation allowed investigation
for opioid synthesis, yet, despite many efforts since its
8
of the chemistry of oripavine for the first time. In order
1
discovery more than 60 years ago no simple method for
to demonstrate its potential use in opioid synthesis, it
was necessary to compare the chemistry with that of
thebaine. The two most important reactions of thebaine
are the oxidation to 14-hydroxycodeinone, leading to the
opiate antagonists, and the Diels-Alder reactions leading
to the orvinols, a class of very potent and important
opioid drugs.2 As expected, it was found that the
chemistry of oripavine is very similar to that of thebaine.
Unoptimized oxidation of the oripavine dienol ether
system to give 14-hydroxymorphinone (3) proceeded in
obtaining it has been described. The corresponding
methyl ether, thebaine (2), a relatively abundant opium
6
2% yield with m-chloroperbenzoic acid under modified
alkaloid and obvious starting material for 1, is widely
used as a raw material for the synthesis of many
medically important opioids.2 Since the vast majority
of these thebaine derivatives are 3-phenols like oripavine,
a frequently troublesome demethylation step is required
that could be avoided if oripavine were available as a
starting material. Oripavine occurs in extremely minor
quantities in opium, and the only available synthesis
requires four steps from morphine.4 A one step O-
demethylation of thebaine to oripavine has thus been an
important goal in the chemistry of the opium alkaloids.
1
3,14
conditions to those described for thebaine,
and Diels-
Alder reaction with 1-buten-3-one gave the orvinone (4)
,3
82%).7
,15
(
Previous attempts5-7 at this conversion have been unsuc-
In summary, we have demonstrated that L-Selectride
allows a practical O-demethylation of thebaine to oripa-
vine in reasonable yield without chromatography and
that oripavine has the potential to be a useful intermedi-
ate in the synthesis of novel opioids. The general ap-
plication of this 3-O-demethylation procedure to opium
alkaloids and their derivatives will be the subject of a
future paper.
cessful, due to the sensitivity of the allylic and dienol
8
,9
ether functions to acids, bases, and nucleophiles.
We
now wish to disclose that this transformation can be
accomplished conveniently by the use of L-Selectride
(Aldrich).
L-Selectride has recently been reported as an efficient
O-demethylating agent for simple systems.1
0,11
We en-
visaged that this reagent may allow 3-O-demethylation
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data (2 pages).
†
University of Bristol.
J O961473K
(1) Konowalowa, R.; Yunussoff, S.; Orechoff, A. Ber. 1935, 68, 2158.
2) Casy, A. F.; Parfitt, R. T. Opioid Analgesics; Plenum Press: New
(
York and London, 1986.
3) Casy, A. F. The Steric Factor in Medicinal Chemistry; Plenum
(10) Majetich, G.; Zhang, Y.; Wheless, K. Tetrahedron Lett. 1994,
35, 8727.
(11) Mathis, C. A.; Mahmood, K.; Huang, Y.; Simpson, N. R.; Gerdes,
J . M.; Price, J . C. Med. Chem. Res. 1996, 6, 1.
(12) Oripavine was isolated as the oxalate salt from methanol.
Thebaine was isolated as the (+)-tartaric acid salt from methanol.
(13) Hauser, F. H.; Chen, T.-K.; Carroll, F. I. J . Med. Chem. 1974,
17, 1117.
(
Press: New York and London, 1993; pp 429-465.
(
(
4) Barber, R. B.; Rapoport, H. J . Med. Chem. 1975, 18, 1074.
5) Andre, J . D.; Dormoy, J . R.; Heymes, A. Synth. Commun. 1992,
2
2, 2313.
(6) Lawson, J . A.; Degraw, J . I. J . Med. Chem. 1977, 20, 165.
7) Hori, M.; Kataoka, T.; Shimizu, H.; Imai, E.; Iwamura, T.;
(
Nozaki, M.; Niwa, M.; Fujimura, H. Chem. Pharm. Bull. 1984, 32,
268.
8) Bentley, K. W. The Chemistry of the Morphine Alkaloids;
Clarendon Press: Oxford, England, 1954.
9) Bentley, K. W. J . Am. Chem. Soc. 1967, 89, 2464.
(14) It was found that oxidation of the dienol ether system with
m-CPBA proceeded smoothly in water at room temperature in the
presence of 1 equiv of sulfuric acid. Under these conditions thebaine
gave 14-hydroxycodeinone in 87% yield.
1
(
(
(15) Brown, J . J .; Hardy, R. A.; Roth, C. N. US Patent 3562279, 1971.
S0022-3263(96)01473-9 CCC: $12.00 © 1996 American Chemical Society