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50981990 Bromomorphide Hydrogenation to Dihydrodesoxymorphine

50981990 Bromomorphide Hydrogenation to Dihydrodesoxymorphine

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Sepl:.,
193:3
HYDROGENATION
F
THE
HALOGENOMORPHIDES
:WJ3
Summary
The aryl thiazolidones studied correspond to the 2-arylamino or stableforms of Wheeler and Johnson.Their sodium salts with methyl or ethyl iodide yield a mixture
of
2-
alkyl-?-aryl and of 3-alkyl-2-aryl thiazolidones. With benzyl chloride onlythe ,"-benzyl derivative has been found.These results have failed to confirm the formulation of Beckurts andFrerich, who assumed that the products they obtained were 2-alkylimino-%aryl thiazolidones. Further unpublished investigations in this Labora-tory support our experimental results.
LAWRENCE,
ANSAS
RECEIVED
UNE
12,
1933
PUBLISHED
EPTEMBER
,
1933
[~OPJ.TRIBUTION
NO.
115
FROM TEIE
COBB
CHEMICAL
LABORATORY,
NIVERSITY
OF
VIRGINIA
The Catalytic Hydrogenation
of
the Halogenomorphides
:
Dihydrodesoxymorphine-D
BY
LYNDON
.
SMALI,,
ECHEE
C.
YUEN
AND
LOUIS
K.
EILERS
In
a previous paper from this Laboratory2 it was shown that catalytichydrogenation of the halogenocodides yielded, according to the conditions,varying amounts of three hydrogenated desoxycodeine derivatives. Byempirical selection of the proper catalyst and solvent, it was possible todirect the hydrogenation in such
:t
way that the non-phenolic dihydro-desoxycodeine-D
(IV)
was the principal product obtained from any of thefour known halogenocodides.
Dihydrodesoxycodeine-D,3
and its un-saturated analog, desoxycodeine-C
(11),4
in both of which the 4,5-etherbridge is still intact, are of particular interest pharmacologically, since theydiffer structurally from certain codeine derivatives (dihydrocodeine andpseudocodeine, respectively) only
in
having
a
hydrogen atom in place ofthe alcoholic hydroxyl of the codeine series. The demethylated analog ofdesoxycodeine-C, namely, desoxymorphine-C
(I),
which may be regardedas a (derivativeof y-isomorphine, has already been de~cribed,~nd has been
found
extraordinarily active in the animal body. With the view of pre-paring a dihydrodesoxymorphine of the dihydrodesoxycodeine-D type,corresponding in fundamental structure to dihydromorphine (Paramor-fan), the catalytic hydrogenation of the halogenomorphides
has
beeninvestigated.
(1)
This investigation was supported
by
a grant
from
the Committee
on
Drug Addiction
of
the
National
Research Council from
luuds
provided
b:?
the Bureau
of
Social
Hygiene,
Iuc
,
and
the
Rocke-
feller Foundation.(2) hlosettig, Cohen
and Small,
THIS
OURN~II,,
64,
793 (1032).(3) Small and Cohen,
ibid.,
63,
2227
(1931).
(4)
Small and Cohen,
ibid.,
63,
214
(1931).
(5)
Small and
Morris,
ibid.,
66,
2874 (1933).
 
3864
LYNDON
.SMALL,
ECHEE
C.
YUEN
ND
LOUISK.
EILERS
VOl.
525
The three known halogenomorphides, on catalytic hydrogenation underidentical conditions, yield varying amounts of three different products.a-Chloromorphide, in methyl alcoholic or weakly acid solution, giveslargely the desired dihydrodesoxymorphine-D (111), together with some
tetrahydrodesoxymorphine
and a little non-crystalline material. In thecase of 0-chloromorphide, the product is almost exclusively dihydrodesoxy-morphine-D. Bromomorphide which
is
believed (without good evidence)to correspond in structure to P-chloromorphide, yields, on the other hand,only small amounts of dihydrodesoxymorphine-D and a large quantity(up to
70%)
of an uncrystallizable oil. This oil could not be distilled
in
high vacuum at any reasonable temperature, which led
us
to believe thatit might correspond in structure to
bis-dihydrodesoxycodeine.
Decisivechemical evidence
on
this point could not be obtained, for the productresulting from methylation of the oil gave only one methiodide (amor-phous), containing one atom of iodine to one molecule of desoxycodeine base
;
this does not necessarily exclude a dimolecular structure.
An
attempt toprepare a
bis-dihydrodesoxymorphine
for comparison, by demethylation
of
bis-dihydrodesoxycodeinewith hydriodic acid, resulted in
a
phenolic basecontaining iodine.The discrepancy between the hydrogenation
of
0-chloromorphide andthat of bromomorphide has
its
parallel in a similar observation in the halo-genocodide series, but does not permit of any valid conclusion concerningthe structure
of
the two halogenomorphides, since the mechanism of thehydrogenation of these halogeno derivatives is uncertain.6 The change
in
reduction conditions, from base in organic solvent to the salt in dilute acidsolution, does not produce
as
great an effect on the course of hydrogenationas
was
observed in the halogenocodide series. For the halogenomorphides,faintly acid solution increases somewhat the yield of tetrahydrodesoxy-morphine, and decreases the amount of oily product formed. In the caseof the halogenocodides, good yields of dihydrodesoxycodeine-D could beobtained only by hydrogenation in acid solution, and in alcohol tetrahydro-
TABLECATALYTICYDROGENATION
F
THE
HALOGENOMORPHIDES(Palladium on Barium Sulfate as Catalyst)
Substance
Tetra-Dihydrodesox hydrodesoxy-
Solvent Moles
Hz
morphine-D,
%
morphine,
%
Oil,
%
a-Chloromorphide Methanol 1.86 70
11"
19
a-Chloromorphide Dil. HCl 2.27 56 33
11
8-Chloromorphide Methanol 2.0 100
..
..
8-Chloromorphide Dil. HC1 2.28
8.7
17
Bromomorphide Methanol 1.86
3
0 a
70Bromomorphide Dil. HCl
1
87
63
5
3
2
a
Trace of unidentified baqje
of m.
p. 275-277"
(6)
Ref.
2,
p.
795
 
Sept.,
1933
HYDROGENATION
F
THE
HALOGENOMORPMDES
3865
desoxycodeine or
bis-dihydrodesoxycodeine
esulted almost exclusively.In
a
repetition of some
of
the experiments
of
Mosettig, Cohen and Small,however, we have found that the results
of
hydrogenation often dependupon unrecognizable slight differences in catalyst or conditions,sothat thediscrepancy between the morphide and codide series may be largely illusory.
:Dihydrodesoxymorphine-D,
the principal product from the hydrogena-
tion
of
a-
and P-chloromorphides, is a colorless, well-crystallized base ofm. p.
188-189’.
It
occurs also in a hemihydrated form of lower meltingpoint, which can be converted to the anhydrous
form
by sublimation inhigh vacuum.
It
is not the same as the “dihydrodesoxymorphine” (m. p.
183’)
of Knoll and CO.,’ for the latter is beyond doubt identical with des-oxymorphine-C (m. p.
189-190‘)
.8
The structure of dihydrodesoxy-morphine-D is evident from its methylation, which leads to the non-phttnolic dihydrodesoxycodeine-D
(IV)
.
Furthermore, dihydrodesoxy-morphine-D can be obtained as the hydriodide in
93%
yield from demethyla-tion of dihydrodesoxycodeine-D. In view of the difficulty of preparationof the halogenomorphides, this constitutes the most practicable preparativemethod, for dihydrodesoxycodeine-D can be made quantitatively fromthe easily accessible a-chlorocodide. Dihydrodesoxymorphine-D can alsobe prepared by “normal” reduction of desoxymorphine-C under the specialconditions developed by Lutz and Small0 for partial hydrogenation ofpseudocodeine types.
N-CHs
H2
/--
\
I10
/
I. Desoxymorphine-C
I
11. Desoxycodeine-C
i
J
c1
111. Dihydrodesoxymorphine- D IV. Dihydrodesoxycodeine-D
(7)
Knoll
and eo., German Patent 414,598 (1922);
Pricdliinder.
16,
1518;
Jahresbcr. Chcm.
Tech.,
71,
123 (1925).
(8)
Small and Moms,
THIS
JOURNAL,
66,
2878 (1933). Although desoxymorphine-C and dihy-drodesoxymorphine-D show the same melting point, an identity
of
these two substances does not comeinto question,
for
they differ in other physical properties, and give a mixed melting point depression
of
15”. Moreover, desoxymorphine-C can be hydrogenated with extreme ease, while dihydrodesoxy-morphine-D is indiflerent to catalytic hydrogenation.
--
(9)
Lutz and Small,
ibid..
64,
4715 (1932).

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