Towards an efficient preparation of hydromorphone

Article abstract of DOI:10.1055/s-0031-1291151

Dihydromorphone was prepared from morphine in high yield, excellent purity, and low residual metal content. The key steps used palladium on porous glass and a modified Oppenauer oxidation, or Wilkinson's catalyst. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0031-1291151

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PRACTICAL SYNTHETIC PROCEDURES
pTraoctiwcalasyrndthesticapnrocEedufrfesicient Preparation of Hydromorphone
Hydromorphone
René Csuk,* Galina Vasileva, Alexander Barthel
Martin-Luther-Universität Halle-Wittenberg, Bereich Organische Chemie, Kurt-Mothes-Straße 2, 06120 Halle (Saale), Germany
Fax +49(345)5527030; E-mail: rene.csuk@chemie.uni-halle.de
Received: 06.03.2012; Accepted after revision: 05.04.2012
Dedicated to Prof. Dr. Wolf-Dieter Rudorf on the occasion of his 70th birthday. Ad multos annos!
PSP
No231
Abstract: Dihydromorphone was prepared from morphine in high yield, excellent purity, and low residual metal content. The key steps
used palladium on porous glass and a modified Oppenauer oxidation, or Wilkinson’s catalyst.
Key words: alkaloids, catalysis, oxidation, reduction, supported catalysis
HO
HO
a
O
O
N
Me
N
Me
HO
HO
2
4
b
c
HO
HO
HO
O
N
N
Me
Me
O
O
1
3
Scheme 1 Reagents and conditions: (a) Pd on porous glass, H2; (b) several Pt or Pd catalysts or Wilkinson’s catalyst; (c) benzophenone, t-
BuOH, toluene.
Opioid analgesics are among the most powerful pain re- scheme starting from morphine (2) yielding 1 in high
lievers. They are used to treat chronic pain (e.g., due to yield and in high purity (Scheme 1).
cancer) or for the treatment of severe acute pain (e.g., fol-
Although 1 has been synthesized by many different
lowing burns, surgery, or very serious injuries after an ac-
routes,2 among them the O-demethylation of codeine or
cident). Hydromorphone (1, Palladone®) is a potent
analogues3 or by microbial transformation4 using strains
of Pseudomonas putida M10 or Bacillus sp., morphine (2)
centrally acting semi-synthetic opioid analgesic drug act-
ing as a μ-opioid agonist.1 This compound is able to cross
seems2 the ideal starting material for the synthesis of 1.
the blood-brain barrier. Thus, it is used as an alternative to
Recently, isomerizations of 2 applying transition-metal
morphine (2) for analgesia and as a side-line narcotic an-
catalysts5–7 or noble metal catalysts6,8 have been claimed
titussive. Its analgesic action is 3–4 times stronger than
in several patents.
morphine, but it shows a lower dependence liability. It
Thus, treatment of 2 or its hydrochloride with catalytic or
stoichiometric amounts of palladium or platinum under a
variety of different conditions gave only low yields of 1.
The amount of 1 in the crude product never exceeded 40%
as determined by HPLC. This finding is in excellent
agreement with previous results.9,10 Invariably under
these conditions the accompanying formation of 3,4-dihy-
droxy-17-methylmorphinan-6-one (3) and dihydro com-
pound 4 took place. Recently, palladium on porous glass
also causes less nausea than morphine. In 2010, in the
USA 3445 kg of 1 were synthesized and available for
medical use. During a project dealing with the synthesis of
labeled 1, we became interested in developing a synthetic
SYNTHESIS 2012, 44, 2840–2842
Advanced online publication: 26.06.2012
0
0
3
9
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7
8
8
1
1
4
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2
1
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DOI: 10.1055/s-0031-1291151; Art ID: SS-2012-T0235-PSP
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Hydromorphone
2841
MS (ESI+): m/z = 288.4 [M + H]+.
has been suggested11,12 as a superior catalyst system re-
placing traditional palladium on carbon catalysts. Howev-
er, using palladium on porous glass, platinum on porous
glass, palladium on graphite, or platinum on graphite13 did
not allow the exclusive formation of 1. Although the iso-
lation of pure 1 is possible by chromatography, the purifi-
cation of crude 1 from these mixtures by recrystallization
generally failed. Its purification via a bisulfite addition
product,14 however, worked nicely. Major drawbacks of
these procedures are the low yields. We were not able to
isolate pure 1 in more than 20–25% yield from these reac-
tions. In addition, ICP-MS investigation of 1 obtained
from these reactions showed the presence of 5–14 ppm of
palladium or platinum (by leaching from the solid sup-
port).
Hydromorphone (1) and Hydromorphone Hydrochloride
(1·HCl)
From morphine (2): A soln of morphine (10.45 g, 36.62 mmol) in
anhyd MeOH (105 mL) was heated under reflux for 5 min, and
Wilkinson’s catalyst (0.105 g) was added. The mixture was heated
under reflux for 6 h, cooled to 0 °C for 2 h and filtered. The filter
cake was washed with cold MeOH (5 °C, 4 × 25 mL each) and dried
to yield 1 (6.7 g, 64%). The filtrate was evaporated, the remaining
solids were dissolved in anhyd MeOH (5 mL), cooled to 0 °C for 1
h and filtered. This gave a 2nd crop of material (1.7 g); total yield
of 1: 8.4 g (80%). Compound 1 was obtained as a colorless solid;
purity >99.8% by HPLC (see below); mp 264–266 °C (Lit.2 265–
267 °C); [α]D –192.9 (c 1, dioxane) {Lit.9 [α]D –194.0 (c 1, diox-
ane}; ICP-MS analysis of this material showed residual Rh 7 ppm.
From dihydromorphine hydrochloride (4): A mixture of 4·HCl (9.3
g, 28.7 mmol), benzophenone (10.4 g, 57.4 mmol), and t-BuOK
(17.7 g, 0.16 mol) in toluene (300 mL) was heated for 2 h at 85 °C.
After cooling to 25 °C, 2 M aq HCl (100 mL) was added, the phases
were separated, and the aqueous phase was extracted with Et2O
(100 mL) and pH was adjusted to 8.5 by addition of Na2CO3. After
extraction with CHCl3–i-PrOH (3:1, 2 × 200 mL), the organic phase
is extracted with 10% HCl (3 × 50 mL), and the combined aqueous
In order to access multigram amounts of pure 1, we set out
to develop a robust, simple, and inexpensive synthesis.
The reaction of 2 with Wilkinson’s catalyst,7 advanced
smoothly, and 1 was obtained in 80% yield. No reaction,
however, took place using 2·HCl instead of the free base.
Traces of hydrochloride reduced the yields. ICP-MS anal- phases were concentrated under reduced pressure. The syrupy resi-
due was triturated with MeOH (20 mL), the product began to crys-
tallize, and crystallization was completed by standing at 5 °C for 2
ysis of this material showed residual rhodium (7 ppm).
As an alternative we considered a two-step synthesis. Re-
duction of 2 using palladium on carbon (5 or 10%)9 gave
an excellent yield of 4, however, because of leaching of
the metal, residual palladium was found (>10 ppm). Re-
duction of 2 using palladium on porous glass proceeded
nicely and gave an almost quantitative yield of dihydro 4
showing low residual palladium (<3 ppm).
h. The product was collected, washed with EtOH (10 mL) and Et2O
(20 mL), and dried to give 1·HCl (6.8 g, 74%) as a colorless solid;
purity >99.9% {HPLC [Lichrocart RP18, 22 °C, 4 × 250 mm,
MeCN–H2O, 35:65 + SDS (0.5% w/v) + AcOH (0.4% w/v), 1.0
mL/min, λ = 240 nm]: tR = 23.5 min}; mp >280 °C (dec.) (Lit.20
280–295 °C); [α]D –129.6 (c 0.50, H2O) {Lit.21 [α]D –132.0 (c 2,
H2O)}. ICP-MS analysis of this material showed residual Pd <0.1
ppm.
1H and 13C NMR spectra correspond to that in the literature.22
Whereas oxidation of 4 using activated manganese diox-
ide, potassium permanganate, or platinum(IV) oxide/oxy-
gen failed, an Oppenauer oxidation using modified
Woodward/Rapoport conditions9,15 yielded target com-
pound 1 in 74% yield without the need for an extra recrys-
tallization. The material obtained by this procedure
showed a purity of >99.9% as established by HPLC.16
ICP-MS analysis of this material showed residual palladi-
um <0.1 ppm.
MS (ESI+): m/z = 286.4 [M + H]+, 570.9 [2 M + H]+, 592.9 [M +
Na]+.
Acknowledgment
We like to thank Dr. R. Kluge for the MS spectra, Dr. D. Ströhl for
the NMR spectra, and Biosearch Technologies Inc. (Steinach,
Germany) for a generous donation of porous glass.
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PRACTICAL SYNTHETIC PROCEDURES
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Synthesis 2012, 44, 2840–2842
© Georg Thieme Verlag Stuttgart · New York