Note: Descriptions are shown in the official language in which they were submitted.
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~his invention xelateæ to an improved procQ~s
for preparing apomorphine and its derivatives by rearrange-
ment o~ the corra~ponding mwrphine derivative.
Apomorphines are very valuable compounds or u~e
in medicine as em~tics~ hypoten~ive agents and CNS stimu-
lant~ (Archer, U.S~ Patent 3,717,643 patented ~ebruary 20,
1973) or in the treatment of Parkinqonism ~German Application
2,154,162, published May 3, 1973). While apomorphines have
been succes~fully synthesized in the laboratory ~see for
n example Sp~th and Hromatka, Ber. 62, 325 (1929); Avenarius
and Pschorr~ BerD 62, 321 (19291, whose claim to a total
~,vnthesis has however been challenged by Gulland, Chem. and
Indr 16~ 774 ~1938); Neumeyer et al., J. Med. Chem. 16,
1223 (1973) and Neumayer et al., J. Med. Chem. 16, 1228
(1973)]~ none of the methods so far devised are commercially
feasible, since they all involve multiple synth~tic steps
and ~urthermore ~equire resolution of optical isomers at
some stage in the ~nthesi~0 The classical morphine/apo~
morphine rearrang~ment thu~ remains the most practical
2~ source of apomorphines, since derivatives of naturally
occurring morphine or its relatives (e.g. heroin or codein~)
are readily available, can be conveniently derivatized
by ~imple chemical trans~ormations either prior or sub-
sequent to rearrangement, and during rearrangement maintain
the natural steric configuration of the only original
22
asymmetric cen~er which i~ not destroyed by khe rearrangement.
The u~e of a variety o~ acids to effect the
morphine/apomorphine type rearrangement by heating the corre-
sponding morphine derivative with the acid is known, ~ luding
S concentrated aqueous zinc chloride solutions [Mayer, Ber. 4,
121 128 (1871) - apomorphine (no yield given~; Matthiessen
et al., Ann. 158, 131-135 (1871~ - apocodeine ~no yield
given); German Patent 489,185, Frdl. 16 ~II), 2485-2486
(1927-1929) - apocodeine (25~ yield) and apomorphine ethyl
ether ~2~ yield)~,concentrated hydrochloric acid [Matthiessen
et alO, Proc. Roy~ SocO ~London) B17, 455-462 (1869) - apo-
morphine (no yield given~0 anhydrous o~alic acid [Knorr
et al3~ BerO 40, 3355-3358 (1907~ - apocodeine ~no yield
given), Folker~, J~ Am. ChemD Soc, 58~ 1814-1815 ~1936~ -
apocodeine (12.8% yield); Corrodi et alO ~ HelvO ChimO Acta.
38, 2038-2043 (1955) - norapocodeine ~13% yield~, 85~ or 90%
phosphoric acid with current of anhydrous hydrogen chloride
passed through mixture ~Oparina, ~him Farm~ Promn 15,
18-19 (1934~, U~SDS~R~ Patent 40,981 ~January 31, 1935);
CoA~ 30~ 7285 ~1936~ - apomorphine (40-42%~; Hensiak, J~
Med, Chem~ 8, 557~559 (1965~ - N-allylnorapomorphine (46%
yield~]~ 85% phosphoric acid with current of nitrogen
passed through mixture ~Koch et al., JO MedO Chem. 11, 977-
981 ~1968) apocodeine (20% yield~, norapomorphine ~13~
yield), N-eth~lnorapomorphine ~36% yield~, N-propylnorapo-
morphine ~37% yield), N-propargylnorapomorphine ~20~ yield),
N-cyclopropylmethylnorapomorphine ~33% yield~, N-benzylnor-
apomorphine (37~ yield), N~phenethylnorapomorphine ~16%
yield)], aqueous glacial phosphoric acid ~ ~PO3)n -See
Merck Index-Eighth Edition, page 824~ ~Wright~ JO Chem,
-3-
~o~z~zz
SocO 25, 652-657 ~1872) - apomorphine (006% yield~] and
glacial pho~phoric acid [Small et al", J, Org, Chem, 5, 334-
349 (1940~ - apocodeine ~30~ yield~] 7
It has now been surprisingly found that apomor-
phines, such as apomorphine it~elf or apocodeine, or norapo-
morphine deriva~ive~, can be preparPd in vastly improved yield
over wha~ was previ~u61y available u~ing prior art proces~es
by heating a corresponding morphine or norm~rphine derivative
with anhydrous orthophosphoric acid (H3PO~) under a partial
vacuum at a temperature at which the rearrangement from the
compound of Formula I to Formula II occurs, the pres~ure
being selected with the temperature such that the orthophos-
phoric acid does not appreciably evaporate during the course
of the reaction~ The apomorphines and R2~norapomorphine~
:L5 prepared by the present proce~s are those having the Fo~nula I:
OH
R~
where Rl i8 hydrogen or lower-alkyl, and R2 i8 hydrogen,
l~wer-alkyl, lower-alkenyl, lower-alkynyl, phenyl-lower-
alkyl or cycloalkyl-lower-alkyl from corresponding morphine
derivatives o~ the Formula II:
~ H oo~II
where Rl and R2 have the meaning~ given aboveO A
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3L0~2122
particularly pre~erred group of apomorphines and ~2-norapo-
morphines prepared by the present process are those of
~ormula I, where R1 is hydrogen or lower alkyl; and R2 is
lower-alkyl or phenyl-lower~alkyl~
~sc~ q//'1
The process of the invention is~carrie~ out by
heating the compounds of Formula II~ in anhydrous ortho-
phosphoric acid ~H3PO4~ at a temperature in the range from
about 125 to 140C~ under a partial vacuum~ While the
practical lower limit to the operable pressure that can
be used cannot be precisely defined, the pressure and
temperature obviously should be such that the phosphoric
acid is not evaporated off during the course of the reaction.
: In practice it has been found that a vacuum obtained from
a water aspixator vacuum pump ~i eO about 9 to 20 mm.Hg~
is entirely suitable~ In some instances~ the reaction
mixture tends to froth in the early minutes of the reaction,
and such frothing is best controlled by increasing the
pressure slightly until the frothi.ng subsides. Thus it
may be nece~sary to use pressures up to about 50 or 60 mm Hg
in the early minutes of the reactionO The rearrangement is
usually completed in about 12 25 minutes, and it is
advantageous to terminate the reaction and work up the
product as soon as the xearrangement is aomplete~ The
course of the reaction ls readily followed by thin layer
chromatography, and since the products of the reaction are
all known, they can be identified, for example, by
compaxison of their melting points with the known melting
point value for the conpounds or by mixed melting point
determinations a
A~ used herein the term lower-alkyl means a
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saturated hydrocarbon group, which may be straight or
branched, ~ontaining from one to five carbon atoms. The
term thus includes, but i~ not limited to, methyl, ethyl,
prop~l~ isopropyl, hutyl and amyl~
The term lower~aLkenyl means an unsaturated
radical having one double bond~ which may be straight or
branched, and containing from three to five carbon atoms.
The term thus incJ.udes, but is not limited to, l-t2-propenyl),
1-(2-meth~l-2-propenyl~ 3-meth~1-2-butenyll or 1-~2-
butenyl~.
The term lower-alkynyl means an unsaturated
radical having one triple bond~ which may be straight or
branched, and containing from three to five carbon atoms.
The term thus includes, but is not limited to, 1-~2-propynyl),
1-~2-methyl-2 prop~nyl~ 3~methyl-2 butynyl~ or 1-~2-
butynyl).
The term cycloalkyl means a saturated carbocyclic
group c~ntaining from three to six ring carbon atoms as
illustrated, for exampleO by cyclopropyl, cyclobutyl, cyclo-
pent~l~ cyclohexyl, 2~methylc~cl~utyl or 4-ethylcyclohexyl~
The process of the present invention is illustrated
b~ the following descriptionO
EXAMPLE
A series of morphine/apomorphine rearrangements
was carried out under five sets of process conditions
designed to compare the yields obtained under the conditions
of the present invention tCondition D~ either as compared
with conditions used in the prior art tCondition A Koch
et al,) or under conditions designed to determine the
effect of other single reaction parameters such as the
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3L0~92~LZ2
nature oi the acid used (Condition B) or combinations of reac~ion parameters
such as the use of nitrogen, a vacuum or anhydrous vs. 85% phosphoric acid
(Conditions C and E). These reaction conditions are as follows:
Condition A- The starting material was heated with 85% orthophosphoric acid
while passing a stream of nitrogen through the mixture.
Condition B- The starting material was heated with 85% orthophosphoric acid
under water aspirator vacuum.
Condition C- The ~5% orthophosphoric acid was flushed with nitrogen while
L
heating, and rearrangement was then carried out with heating under applica-
tion of a water aspirator vacuum.
~ondition D- The starting material was heated with anhydrous orthophos-
. .
phoric acid under a water aspirator vacuum.
Condition E- The starting material was heated with anhydrous orthophosphoric
acid while passing a stream of nitrogen through the mixture.
In each case the starting material was added to the phospho-
ric acid after the latter had been heated to 70C. When reaction was com-
plete in each case, as indicated by thin layer chromatographic analysis, each
reaction mixture was worked up according to a standard procedure which is
described as follows: The reaction mixture was poured into 600 ml. of ice
water and allowed to stand overnight. The working up includes hydrolysis
of the phosphate ester formed (by the reaction with the phosphoric acid) by
reaction of said ester with water, which hydrolysis is substantially the same
as that carried out on the corresponding phosphate esters formed by the reac-
tion with the 85% or 90% phosphoric acid as taught in Hensiak and Koch et al.,
acknowledged above. The mixture was then heated to boiling for fifteen
minu~es, to insure complete hydrolysis of the phosphate esters, then cooled
and poured slowly into 650 ml. of saturated brine. The aqueous layer was
decanted from the gum which formed, and the gum was dis
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''~;
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solved in 400 ml~ o~ water and made ba3ic by the addition of
sodium sulflteO ~h~ mixture wa~3 then extracted wi~h isopropyl
acetate, the organic solution filtered, dried over anhydroua
calcium sulfate and then acidified with ethereal hydrogen
chlorideO The hydrochloride salt which thus ~ormed was
collected, ~ecrystall1z~d from an appropriate solvent,
identi~ied by its melting point and weighed, The re~ults
obtained, expressed in terms of percent yield, are given
in th~ following tabl~s where the react~on condition used,
i~e~ Conditions "A"9"B","C","D", or "E", and the maximum
temperature and the total time of heating are given.
Result~ obtained in a series of runs for the
rearrangem~nt of N-propylnormorphine to N prop~lnorapo-
morphine are given in the following table The product in
15 eaah case was recry~tallized from n-butanolO
Run CondO ~ ~ Yield
__ __
1 A 142~41 49~0
2 A 142/38 50O8
3 A 145~75 39 2
4 A 142/44 21O7
A 142/45 33 0
6 A 143/55 30.1
7 A 148/50 33.9
8 A 145/S0 13.2
9 A 145/4Q~ 33 9
10-1 A l45/4 ~ ¢a~ 9 4
11 A NoAo (b~ 15.4
12 A 145/20 24,1
13 A 145/25 16~3
14 A 140/18 23~6
AVERAGE YIELD
1 B 140/25 3231
2 ~ 130/13 2~.3
AVERi~GE YIEI-D
C 130/10 41 . 6
2 C 130/13 ~2.5
AVERAGE YIELD 7
1 D 130/15 53,5
-8-
z~z
Run Cond 9 Max~C~/Time~min ~ % Yield
__ _ ~ __
2 D 128/13 40,6
3 D 132/13 46O8
4 D 132/17 43 6
D 134/15 50 1
6 D 130/15 39 5 3
7 D 130/15 48.6
8 D 128/16 49~1
9 D 130/15 58~6
~ D 130~15 5191
AVERAGE YIELD~c)
1 E 150~25 22.6
2 E 150/25 21.8
AVERAGE YIELD ~
~a~ Two runs~ Yield based on combined products.
(b) Not available
(c~ Does not include two runs in which products
were worked up in a totally different manner than
the standard procedure and atypical yields, 30,2
and 23,6% respectively, obtained.
Results ohtained for the rearrangement of codeine
to apocodeine are given in the following tableO The product
in each case was recrystallized from water,
Run Cond~ ~ ~ % Yield
1 A 145/A5 19~7
2 A 145/45 17.2
3 A 140/4,0 18~3
~VERAGE ~IELD ~
1 D 140/20 59~2
2 D 140/25 70O5
AVERAGE YIELD ~~
Resulks obtained in the rearrangement of morphine to
apomorphine aré given in the following table. The products
35 in each case were recrystallized from isopropyl acetate/
diethyl ether.
Run Cond. ~ % Yield
_~ ___ __
1 A 140~45 10,0
2 A 140/45 14,0
~VERAGE YIELD
1 D 130/14 58.4
2 D 130/15 54.6
AVERAGE YIELD ~5~5~~
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Results obtalned ~or the rearrangement o~ N-phenethyl-
normorphine to N-phenethylnorapomorphine are given in the
following table~ The products in each case were recrystal-
lized from isopro~l acetatejdiethyl ether.
Run Cond~MaxOT~C0 ~ % ~ield
1 A 138/45 25~4
2 ~ 138/~5 22Og
AVERAGE YIELD ~
1 D 130/15 6~,0
2 D 130~15 68.0
AVERAGE YIELD ~
1 E 150j40 53,0
2 E NoA~ 61,0
3 1 E ~A~ 150/~5~
3~2 ~150/25 ~ 35.6
A~IERAGE YIELD ~3~
The~e results show thatO under the conditions of the
instant proGess~ iOeO reaction Condition D, the yield
obtained in the morphine~apomorphine rearrangement for a
variety of morphine der~vatives is in the range ~rom
about 48 66~, In contrast the conditions used in the
~rior art (i,eO Condition A -~ Koch et alO~ afford yields
in the range from 12-28~o
1 0
