Note: Descriptions are shown in the official language in which they were submitted.
49~
The present invention relates to novel 2-tetrahydro-
furfuryl-6,7-benzomorphanes, their acid addition salts
and processes for their preparation. The novel compounds
possess interesting physiological properties.
According to one feature of the present invention
there are provided compounds of the general formula:-
2N '_CH2 1 o~J
~R ~ I
R~10 1 ''
(wherein Rl represents a methyl, ethyl or propyl group;
R2 represents a hydrogen atom, or a methyl or ethyl group;
R3 represents a hydrogen atom or a methyl group; R~
represents a hydrogen atom, an alkyl group with l to 4
carbon atoms or an acyl group with 2 to 5 carbon atoms)
and acid addition salts thereof.
In the compounds of formula I according to the
present invention the radicals Rl and R2 are arranged
in the cis position with reference to the carbocycllc
ring. Thus where Rl and R2 each represent an alkyl
-- 2
.
., , :. . :
. . ~ ., . - : , :
~al495~
group and R3 does not represent the same atom or group
as R2, the present invention only relates to the
~-benzomorphanes, Rl and R2 being in the cis position.
The acid addition salts useful for incorporation
in pharmaceutical compositions are physiologically
compatible acid addition salts. Other acid addition
salts may however be useful in the preparation of
compounds of formula I and the phys;ologically compatible
acid addition salts thereof.
As will be appreciated from the a~ove-identified
definition of the compounds of formula I, the stereochemi-
stry of these compounds is as follows:- ~
The norbenzomorphane of the formula -
~ 2 II
R4 ~1
on which the compounds of formula I are based, possesses
2 asymmetric carbon atoms when R2 and R3 represent
the same atom or group and 3 asymmetric carbon
atoms when R2 and R3 do not represent the same atom or ~
group. 3 ;
: , ' ' , " ,; . ~ ' , ", ' ' '
1~495~
As a result of the rigid arrangement of the C
and C5 asymmetric carbon atoms in the bridged ring
system and as a result of the fixing of the C9 asymmetric
carbon atom (restriction to the ~-range), the nor-compounds
of formula II on which the compounds of formula Iare based
exist only in a single racemic form and in the form of
the corresponding optically active isomers.
Designation Form of II Configuration
(+) - II racemic _
(-) - II laevorotatory 1 R, 5 R, 9 R
(+) - II dextrorotator) I a, 5 S, 9 ~
.
When the compound of formula II carries the -
N-tetrahydrofurfuryl substituent i.e. as in the compounds
of formula I,an additional assymetric carbon atom
appears in the molecule (at C2" in the tetrahydrofuran
ring). It is, therefore, to be expected that the above
defined compounds of formula I exist in the form of two
different racemic diastereoisomers[(I,l~ and (I,2)] as
well as in the form of the corresponding optically active
isomers, as a result of the existence of the following
combination of possibilities.
;'
95i~
rDesignatlor Configuration 1
~, . .. _.
benzomorphane N-tetrahydro-
furfuryl grou
_ ~ __ _ _ _ _ . .
I,lR, 5 R, 9 R-(-) D-(-) racemic dia-
S, 5 S, 9 S-(+) L-(+) stereoisomers
I,2R, 5 R, 9 R-(-) L-(+) racemic dia-
__ _ 1 5, 5 S, 9 S (+) D-(-) stereoisomers
In principle it is not possible to forecast which
of the optically active isomers pertaining to (I,l)
or to (I,2) is laevorotatory and which is dextrorbtatory - -
solely upon the configuratlon. Such a determination may ;
only be made by measurement in a polarimeter. --
We have, however, closely examined 2-tetrahydro-
furfuryl-2'~hydroxy-5,9~-dimethyl-6,7-benzomorphanes accor-~-
ding to the invention (i.e. compounds of formula I wherein
Rl = R2 = CH3 and R3 = R4 = H), and we have found that
the direction of rotation of the basic compound of
formula II is not altered by introduction of the D-(-)
or L-(~)-tetrahydrofurfuryl group. It is probable,
but cannot ~e predicted with certainty, that this finding
is also true for compounds of formula I in which Rl,
R2' R3 and R4 represent different atoms or groups.
- 5
95~1
As far as the nomenclature of the compounds of
formula I is concerned, there is no difficulty in
representing the optically active isomers, as can be
seen from the above table. If the nomenclature IR,
5R, 9R or lS, 5S, 9S is used, the configuration at Cg
is fixed clearly and the "a" may be omitted in the
chemical designation. With the racemic compounds of
formula I, however, it cannot be predicted which of the
two possible diastereoisomers is present. In the
present complete specification both the racemic
diastereoisomers are designated by (+) and are
differentiated from one another by the addition of
"diastereoisomers 1" or "diastereoisomers 2" in which l
and 2 represent the sequence of isolation.
The compounds of formula I and the physiologically
compatible acid addition salts according to the invention
exhibit interesting physiological properties and in
particular exert a therapeutically useful effect upon
the central nervous system. Compounds of the present
invention which have been tested have been found to possess
a pronounced analgesic effect which may, for example,
be demonstrated in the mouse by the ~rithing test,
the hot-plate test and the Haffner test. The most -
effective compounds of the present invention which were
tested were found to possess an analgesic effect ten to
thirty times greater than the analgesic effect of - ;
morphine, the compounds being administered by sub-
cutaneous injection. In spite of the good analgesic
activity of compounds of the present invention the
side-effects typical of morphine, e.g. the Straub tail
phenomenon and the locomotor effect are, in general, absent.
: . .
The absence of these side-effects, particularly in relation
to compounds active in the Haffner test, suggests that
other undesired properties associated with morphine are
also absent, e.g. the addictive properties of morphine.
The connection between the Straub~tail phenomenon and
addiction potential has been documented in the literature;
see I. Shemano and H. Wendel: A Rapid Screening Test ;~
for PotentialAddiction Liability of New Analgesic Agents,
Toxicol. Appl. Pharmacol. 6, 334-339 (1964 ). Moreover
in general, the novel compounds possess a greater thera-
peutic scope in comparison to morphine. Moreover, the
compounds according to the present invention do not
-- 7
~634~51~ ~
exhibit any morphine like activity in rats sufEering
from morphine-addiction.
Preferred compounds according to the present
invention, by virtue of their favourable physiological
properties, include compounds of formula I as herein- :
before defined wherein R/ represents a hydrogen atom
and the acid addition salts thereof.
Especially preferred compounds according to the
present invention, by virtue of their espe~ially favourable
physiological properties include compounds of formula I : -
(wherein Rl and R2 each represent a methyl group and
R3 and R/ each represent a hydrogen atom) and the acid
addition salts thereofO These especially preferred
compounds exist, for example, in the following forms~
(-) 2 (D-tetrahydrofurfuryl)-[(lR,5R,9R)-2'-hydroxy- -
5,9-dimethyl-6,7-benzomorphane]-methanesulfonate
~ 2-tetrahydrofurfuryl-2'-hydroxy 5,9a-dimethyl-6,7-
benzomorphane (racemic diastereoisomer I as herein defined)
(+) 2-tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-
benzomorphane (racemic diastereoisomer II as herein
defined)
-- 8
5~
~ 2-(L,tekrahydrofurfur-yl)-[(lR, 5R, 9R)-2'-hydroxy-5,9-
dimethyl-6,7-benzomorphane].
The compounds of general formula I according to the
present invention may, for example, be prepared by one of the
following processes
(a) reacting a co~pound of formula II
R40 Rl
wherein Rl, R2~ R3 and R4 are as defined above, with a compound
of formula III
~ I .:
10/ \ ~ III
X ~ CH2
wherein X represents a group removable as an anion and is
chosen f~om a halogen atom, or an arylsulfonyloxy, aralkylsul-
fonyloxy, or alkylsulfonyloxy group; or .
(b~ reducing a compound of formula IV
~ .
-
~04~5~L~
Y
r ~ O J
r ~\ /R3 , .
~ \~', IV ' '
~, R2
R40 Rl
wherein ~ , R2, R3 and R4 are as defined above, and Y represents
o~ygen, with a complex metal hydride; or
(c) reacting a compound of formula IV
N - C ~ ~ ;
R
R40
wherein Rl, R2, R3 and R4 are as defined above and Y represents
oxygen with phosphorus pentasulphide, and reducing the thus
obtained intermediate with a reducing agent chosen from complex
metal hydrides, nascent hydrogen, hydrogen in the presence of
a hydrogenation catalyst, or by electro-chemical reduction, or
(d) reacting a compound of formula IV
-- 10 --
~495~
'LV ~ ~
R40 : -
wherein Rl, R2, R3 and R4 are as defined above and Y represents
oxygen with an alkyl halide, and reducing the thus obtained inter-
mediate with a reduclng agent chosen from complex metal hydrides,
nascent hydrogen, or hydrogen in the presence of a hydrogenation
catalyst, or
(e) reacting a compound of formula IV
,
R40 Rl : :
wherein Y represents oxygen and Rl, R2, R3 and R4 are as defined
above, sequentially with phosphorus pentasulphide, alkylating
the thus obtained product with an aIkyl halide, and reducing the
alkylated product with a reducing agent chosen from complex
metal hydrides, nascent hydrogen, or hydrogen in the presence of
a hydrogenation catalyst; .
-- 11 --
5~
(f) reacting a compound of fo~nula I:[
r-N H
h3 II
R40
wherein Rl, R2, R3 and R4 are as defined above, with an
alkylating agent chosen from a phenethyl, naphthylethyl or
1,2-diphenylethyl halide; reacting the thus obtained product
with a compound of formula III
~ III
X CH2 /
.
and sub~ecting the thus obtained interm~diate to reaction with
a strong base to provide a compound of formula I; `~
(g) reacting a compound of formulae XI or XII
IRl
~, -R2
N H2 ~ OR4
H
- 12 -
'
1~95~L~
' R2
3 :~
l ~ CH2 ~ ~ ~ OR4
H
'
wherein Rl, R2, R3 and R4 are as defined above and Z represents
a group removable as an anion and is chosen from halogen~ hydroxy,
alkoxy, acyloxy, arylsulfonyloxy or alkylsulfonyloxy, with a
compound of for~ula III
~ ~ III
X CH2
.. . .
wherein X is as defined above3 and cyclizing the thus obtained
product in the presence of a Friedel-Crafts catalyst; or
(h) reacting a compound of rormula II
N H
~ R3 II
W "~
R2
R40 Rl
5~L~
with a compound of formula XIII
Y CH2 CO CH2 CH2 C02C2H5 XIII
wherein Y is as defined above, reducing the thus obtained com-
pound with a complex metal hydride and thereafter cyclizing the
thus obtained intermediate in the presence of a reagent chosen
from sulphuric acid, phosphoric acid, oxalic acid, p-toluene
sulphonic acid, sodium bicarbonate, and anhydrous zinc chloride; or
(i) where a compound of formula I is required in
which R4 is hydrogeng subjecting a co~lpound of formula IX
N CH2 1
~ /R3
IX
/ r `\~ ~2
~ 1
R70
wherein Rl, R2 and R3 are as defined above and R7 represents
an esterifying group derived from an organic or inorganic acid,
to hydrolysis in the presence of either an acid or an alkali or
to hydrogenolysis in the presence of a complex metal hydride; or
(j) where a compound of formula I is required in
which R4 represents hydrogen, cleaving the ether linkage in a
compound of formula X
- 14 -
~9S~
~ CH2 X
R80 ,,
wherein R8 represents an etherifying alkyl or aryl group and
Rl, R2 and R3 are as defined above, by means of acid, or alkali,
or by catalytic hydrogenation whereby the group R8 is replaced
by hydrogen and the tetrahydrofuran ring is left intact; or
(k) where it is desired to convert a compound of
formula I in which R4 is hydrogen, to a co~,pound in which R4 is
acyl, reacting a compound of formula I in which R4 is hydrogen
with the relevank carboxylic acid chlorlde or anhydride; or
(1) where it is desired to convert a compound of
formula I in which R4 is hydrogen to a com~ound in which R4 is
an alkyl group, reacting a compound of formula I in which R4 is
hydrogen with diazomethane or with a trialkyl-ammonium hydroxide, or
~m) if desired, converting a ~ree base of formula I,
or a salt thereof, into a pharmaceutically acceptable salt.
The reduction (a) is conveniently effected using an
equimolar quantity of khe alkylating agent of formula III or
preferably a molar excess thereof and the reaction is advantage-
ously effected in the presence of an acid-binding agent, such as
e.g. triethylamine, dicyclohexylethylamine, sodium carbonate~
potassium carbonate or calcium oxide, but preferably sodium
hydrogen carbonate. Although it is not necessary to effect the ~-
- 15 -
~ : .
.~
,,, .:
~ ~ '
~95~
reaction in a solvent, it is more convenient to carry out the
reaction in an inert solvent, e.g. chloroform, toluene, ethanol,
nitromethane, tetrahydrofuran or dimethylsulfoxide and preferably
dimethylfor~mide. Mixtures of these solvents may also be used.
An excess of the alkylating agent of formula III, for exa~,ple, an
excess of tetrahydrofurfurylbromide, may also serve as the solvent.
The reaction temperature may be varied over a wide range, the
lower temperature limit is set by a too low reaction speed and
the upper temperature limit being set by the increased presence
of side-reactions. The reaction is conveniently effected at a
temperature of from 50 to 150C, preferably at about 100C. If
the reaction is effected using less reactive alkylating agents,
e.g. with tetrahydrofurfurylchloride, the rate of the reaction may
be accelerated by the addition of a catalytic or equimolar quantity
of potassium or sodium iodide.
Reduction of the carbonamides (i.e. compounds of
formulaIVwherein Y represents an oxygen atom) may be effected
according to various methods. Ihe reduction is preferably
effected by the use of a complex hydride of high reducing power,
especially lithium aluminium hydride. ~he hydride is conveniently
employed in an equimolar qu~ntity or in a molar excess, preferably
up to double the molar qu~ntity. The reduction is conveniently
effected in the presence of an inert solvent, preferably diethyl
ether or diisopropyl ether and, in particular, tetrahydrofuran.
The reaction temperature may be varied over a wide range, but is
advantageously from 0 to the boiling temperature of the reaction
mixture.
During the reduction of O-acyl derivatives of formula
IV, (wherein Y represents an oxygen atom) with complex metal
hydrides, e.~. during reduction with lithium aluminium hydride,
not only is the carbonyl group reduced, but the O-acyl group is
- 16 -
.,
'
,r
also reduced such that compounds of formula I are obtained in
which Rll represents a hydrogen atom.
The reduckion of the thioamides (compounds of formula
IV, wherein Y represents a sulfur atom? takes place more readily
than the reduction of the carbonamides. The reduction is pre-
ferably effected by the use of a co~plex hydride or with nascent
hydrogen (e.g. zinc/hydrochloric acid, zinc/acetic acid or
aluminium-amalga~water); it is also possible to deslilfurize the
compounds of formula IV with Raney-nickel or to effect the re-
duction electrochemically. When using a reducing agent with a
stronger reducing power, any 0-acyl groups present may also be
reduced. In this case compounds of formula I resultg in which R4
represenks a hydrogen atom.
Reducing a compound of the formula
-- ~ C =l
An (3
R40 1 n
(wherein Rl, R2~ R3, R4 and Y are as hereinbefore defined, R5 ~ ~ -
represents an alkyl group with up to 4 carbon atoms, A represents
the anion of an inorganic acid and n is the change on the anion),
obtained as an intermediate in process (d) above, may be effected
according to various processes and one may apply, for example,
all those measures referred to above in relation to the reduction
of the thiocarbona~idesj however, as the compounds of formula V
- 17 -
'5~J' j
..1~ .._ .
'
,
~953L~
can be decomposed and tend to give rise to side-reactions (e.g.
hydrolysis, aminolysis) the reduction should be carefully con-
trolled~ some restrictions being made. It has proved advantage-
ous to continue reacting the compounds of formula V immediately
without isolation. The use of complex metal hydrides with a
lower reducing power is advantageous, for example sodium boro-
hydride. Furthermore, it is possible to effect reduction by
nascent hydrogen or by hydrogen in the presence of a hydrogenation
catalyst, e.g. Raney nickel. According to the reaction conditions,
any 0-acyl groups present may be simultaneously reduced in the
course of the reduction.
Reaction of a compound of formula VI
I R6\ ~CH2 -- r' ~ :
r ~; ~n ~ VI
R40
(wherein Rl, R2, R3, R4, N and A are as hereinbefore defined
and R6 represents a ~-phenylethyl, naphthylethyl or 1,2-diphenyl-
ethyl group~, obtained as an intermediate in, for example process
(f), is effected by the action of bases upon the quaternary salts
and may be performed by the use of a variety of methods. Under
the conditions of the Hofmann elimination, any O~acyl groups
present may be simultaneously reduced, whereby corresponding com-
pounds of formula I are obtained, in which R4 represents hydrogen
atoms.
- 18 -
........ ...
~3 ~
. ~ . .
..
~o~9~
q~he cyclization reaction of process (g) may be
effected according to kncwn methods. For example, the cycli~
zation may be effected under the conditions of the Friedel-
Crafts reaction with aluminium chloride e.g. in carbon disulfide
or cyclization may, for exa~,ple, be effected by the use of a
strong acid, such as phosphoric acid or polyphosphoric acid, pre-
ferably at a temperature of from 100 to 150C. Under the reaction
conditions of the cyclization under certain circumstances, 0-acyl
or 0-alkyl groups may simultaneously be reduced, whereby compounds
of formula I (wherein Rll represents a hydrogen atom) are obtained.
me cyclization process according to process (h) may -
be carried out according to various processes. For example~
cyclization n~y be effected by dehydration using an acid catalyst.
Acid catalysts which may be employed to effect cyclization in- ~ -
clude9 for example inorganic or organic acids or acid salts, such
as sulfuric acid, phosphoric acid, oxalic acid, E~toluene-
sulfonic acid, sodium hydrogen sulfate or anhydrous zinc chloride.
Ihe cyclization is preferably carried out at an elevated temper- ~-
ature, especially at a ten,perature of from lO0 to 200C. It may
be advantageous to remove the
- 19 -
~
, .
,~
.. . .
~10495~
water that is formed during the cyclization by water binding
agents, e.g. excess sulfuric acid or zinc chloride or alterna~
tively by azeotropic distillation. As indicated above it is
frequently of advantage to replace one of the two hydroxy groups
by a more reactive group in order to form an intermediate which
is subsequently cyclized. ~hus, for example, cyclization may
be effected with toluene~sulfonic acid chloride in pyridine,
without isolating the toluene-sulfonyloxy-derivative of the
compound of formula VIII that forms as an intermediate.
According to whether relatively drastic reaction conditions are
used, the 0-acyl and 0-alkyl groups may be reduced to free
phenolic hydroxy groups i.e. co~lpounds of formula I (wherein
R4 represents a hydrogen atom).
For the preparation of compounds of formula I as
hereinbefore de~ined (wherein R4 represents a hydrogen atom),
the ester cleavage of a compound of the formula:-
- 20 -
.
- , . . . . . . . .
.~,
s~
/ CH
"r~ R3
\ ~ / `~ R2 IX
~ ~T~ . '.
R
(wherein Rl, R2 and R3 are as hereinbefore defined and
R7 represents an acyl group derived from an inorganic
or organic acid) whereby a compound of formula I
(wherein R~ represents a hydrogen atom) is obtained.
A compound of formula IX is preferably used in
which R7 represents a lower aliphatic or simple e.g. mono~
cyclic aromatic or heterocyclic acyl group, especially
an acetyl, propionyl, benzoyl or tetrahydro-2-furoyl
group.
10~ The ester cleavage may be performed according to
various processes. A most convenient method is acid
or alkaline hydrolysis, which is preferably effected in
aqueous 9 alcoholic or aqueous-alcoholic solution. The
reaction temperature may be varied over a wide range,
but is advantageously from 20 to 100C. r,
- 21
.
5~L
me ester cleavage may also be effected by reduction.
It is advantageous to effect the reduction with a complex hydride.
me reduction is effected in a similar manner to the method de-
scribed for the reduction of the carbonic acid amides in process
(b). It is advantageous to reduce the amide and phenol ester
grouping simultaneously.
For the preparation of a compound of formula I
(wherein R4 represents a hydrogen atom), the ether cleavage of
a compound of the formula:-
N CH2
/ 3
~ ~ X
kl
R80
(wherein Rl, R2 and R3 are as hereinbefore defined and R8 rep-
resents an alkyl or aralkyl group) whereby compounds of formula
I are obtained wherein R4 represents a hydrogen atomO
The ether cleavage of a compound of formula X to
yield a compound of formula I may be effected according
- 22 -
, . .. .
r~
~9s~
to various methods, the methods varying greatly with the nature
of the radical R8 and being chosen in such a way that the
tetrahydrofuran ring remains intact. For example, the selective
cleavage of the phenolether grouping is preferably effected
with caustic soda or caustic potash conveniently in a high
boiling solvent~ such as diethylene glycol or triethylene glycol.
This ether cleavage is conveniently effected at a temperature of
from 150C to the boiling point of the reaction mixture pre-
ferably in the presence of an excess of the alkali metal hydroxide. -
Benzyl ethers may also be cleaved by catalytic hydrogenation.
Methoxymethyl ethers are very unstable with acids and may be
cleaved even under mild conditions with dilute mineral acids.
For the preparation of compounds of formula I
(wherein R4 represents an acyl group with 2 to 5 carbon atoms),
the acylation of a compound of formula I (wherein R4 represents
a hydrogen atom) whereby compounds of formula I (wherein R4
represents an acyl group with 2 to 5 carbon atoms) is obtained.
- 23 -
. , .
-
. .
,
~ ~ 4~
The acylation may be effected according to a
variety of different methods~ It is advantageous to
use a carboxylic acid chloride or a carboxylic acid
anhydride as the acylating agent. The acylation
may collveniently be effected in the presence of an
inert solvent advantageously with a molar quantity
or with a slight molar excess of the acylating agent.
~owever, it is also possible to use an excess of the
acylating agent, which then simultaneously serves as
the solvent. It is preferred to add an acid-binding
agent to the reaction mixture. Pyridine is
preferred for this purpose, and may be employed
in catalytic quantities, in equimolar quantities
or in excess in addition to the solvent. A base which
may also be used for this purpose with advantage is
triethylamine. The reaction is advantageously effected
at a temperature of from 20 to 150C, preferably
from 50 to 100C.
24
,f'~
~0~953L~ ~
~ or the preparation of compounds of formula I
(wherein R4 represents an alkyl group with 1-4 carbon atoms),
the alkylation of a compound of formula I (wherein R4 represents
a hydrogen atom) whereby a compound of formula I (wherein R4
represents an alkyl group with 1-4 carbon atoms) is obtained.
The alkylation may be effected according to a
variety of different methods. Alkylating agents and reaction
conditions are preferred, which allow for selective 0-alkylation
without quatem ation of the nitrogen. For this purpose diazo-
alkanes or phenyltriaIkyl ammonium hydroxides are preferred as
alkylating agents. Where a diazoalkane is used as the alkylating
agent the alkylation is conveniently effected in the presence
of an inert solvent, e.g. diethyl ether or tetrahydrofuran, and
preferably at ambient temperature. Where a trialkylammonium
hydroxide is used as the alkylating agent, the alkylation is
advantageously effected at an elevated temperature and conveniently
in the presence of an inert solvent, preferably in dimethyl-
formamide. The reaction products obtained may, for exan,ple, be
isolated from the reaction mixture by conventional methods.
If required, the crude products obtained may be pvrified using
- 25 -
~
''',
~r.
' '' ~ ' '~ ' ' ,:
,. - , :, '` ~, ~ '
9Sl~
special processes, e.g. column chromatography, before
crystallization in the form of the base or acid addition
salt thereof.
According to the reaction condition and the reactants chosen,
the reaction products are obtained either in the form of
the optically active isomers or in one form of the racemic
mixture or the o~her or in the form of a mixture of the
racemic or optically active diastereoisomers.
Diastereoisomers may be separated, as a result of their
differing chemical and physical properties, according to
known processe3, for example by fractional crystallization.
Racemic compounds may be separated into their corresponding
optically active isomers by any of the conventional methods
of racemate separation. ~;
Many of the starting compounds used for the processes described
above are known. Thus, for example 9 the norbenzomorphanes
of general fonmula II have been described several times
in the literature.
The optically active t~trahydrofurfuryl halides of formula
III may be produced from the known optically active alcohols
(F.C. Hartmann and R. Barker, J. Org. Chem. 29, 873 - 877
[1964]) by halogenation, e.g. with phosphorus pentachloride
or phosphorus pentabromide (Org. Synth. 23 , 88): ~
~.' :
- 26 -
: . ., . .. , ; ,.~ , , ~
~ 5~
L-(+)-tetrahydrofurfuryl alcohol: La]D = + lS.3 (c - 5,
nitromethane)
b.p. 76 / 16 mm Hg
D~ tetrahydrofurfuryl alcohol: [~]D = ~ 15.7 (c = 5,
nitromethane)
b.p. 76~ / 16 mm Hg
L-(+)~tetrahydrofurfuryl bromide: [~]D5= + 3 9 (c = 5,
nitromethane) b.p. 66-67/
16 mm Hg
D-(-)-tetrahydrofurfuryl bromide: L~]D = -3-8 (c = 5,
nitromethane)
b.p. 67 / 16 mm Hg
By reacting the tetrahydrofurfuryl alcohols with sulfonic
acid halides, corresponding sulfonic acid este~ may be
produced.
Carbonic acid amides of general formula IV may, for example,
be obtained by reacting the nor-compounds of formula II
with ~etrahydrofuroyl chlorides. The corresponding
thiocarbonamides may, for example, be produced by reacting
the corresponding carbonamides of formula IV with phosphorus
pentasuIfide.
- 27 -
-, . ~
.
/` -
~ ~9 5~ ~
Compounds of formula V may, for examplebe obtained by
reacting compounds of formula IV with alkylating agents.
Compounds of formula VI may, for example, be produced by
reacting nor-compounds of formula II with ~-phenylethyl
chloride, naphthylethyl chloride or l,2-diphenylethyl
chloride and 9 subsequently, quaternising the tertiary amines
with compounds of formula III.
The starting compounds of general formula VII a or VII b
may,for example, be prepared by alkylating a piperidine
of the formula
Rjl
~,", R2 ' -; ' - '
H CH2 ~3 - OR4
R~
,~ R3
~R2
H CH2 ~ OR4 XII
(wherein Rl, R2 ~ R3, R4 and Z are as hereinbefore defined)
- 2
'
, ,. , ~,. . . .
,~ ~ .,,...... : .:, , ~ ' .
' . . ~. : , , . . : . . . .: ' .
~ 95~ ~
with an alkylating agent of formula III. The piperidines
are known from the literature.
The starting compounds of formula VIII may, for example,
be produced by reacting nor-compounds of formula II with
~-keto-acid esters of formula
2 ,C, CH2 ~ CH2 ~ COOC2H5
XIII
(wherein Y is as hereinbefore defined) and reducing the
intermediate compound of formula
ICH2 CIH2
CH2 / ~ C2H5
N
_ ~
~ R3
R4 / Rl
(wherein Rl, R2, R3 and R4 are as hereinbefore defined)
thus obtained with a complex hydride. .
. - 29 -
.. , ~ "
.....
. !.-.
s~
The starting compounds of formulae IX and X may, for example,
be prepared by alkylating the corresponding norbenzomorphane
with an alkylating agent of formula III.
The compounds of general formula I according to the present
invention are bases and may, if desired, be converted into
their physiologically compatible acid addition salts in
the conventional manner. Acids suitable for salt formation ~
include, for example, mineral acids such as hydrochloric acid, : ~ -
hydrobromic acid, hydriodic acid 9 hydrofluoric acid, sulfuric
acid, phosphoric acid or nitric acid; or organic acids such
as acetic acid, propionic acid, butyric acid, valeric acid, ;
pivalic acid, caproic acid, oxalic acid, malonic acid, :
succinic acid; maleic acid, fumaric acid, lactic acid,
tartaric acid, citric acid, malic acid, benzoic acid,
~aminobenzoic acid, ~-hydroxybenzoic acid, phthalic acid,
terephthalic acid, cinnamic acid, salicylic acid, ascorblc
acid, 8-chlorotheophylline, methanesul~nic acid, ~enzene-
sulfonic acid and ethanephosphoric acid. . ~
According to a still further feature of the present ~ :
invention there are provided pharmaceutical compositions ;~
comprising as active ingredient at least one compound of
formula I as hereinbefore defined or a physiologically
compatible acid addition salt thereof in association with
- 30 -
- . , . . - , . . ...
. ... . . . .
9S~L~ -
a pharmaceutical carrier or excipient~ The compositions
according to the invention may also include, if desired,
other physiologically active compounds 9 for example
sedatives, hypnaeics or tranquilizers.
The compositions according to the inventîon may be presented,
for example, in a form suitable for parenteral or enteral
administration.
The compounds according to the invention may be -~
presented in the conventional pharmacological forms of
administration, such as tablets, coated tablets, solutions,
emulsions, powders, capsules or sustained release forms.
Conventional pharmaceutical excipients as well as the usual
methods of production may be employed for the preparation of
these forms. Tablets may be produced, for example, by
mixing the active ingredient or ingredients with known
excipients~ such as for example with diluants, such as
calcium carbonate9 calcium phosphate or lactose,
disintegrants such as corn starch or alginic acid, binders
such as starch or gelatin, lubricants such as magnesium
stearate or talcum, and/or agents for obtained sustained
release, such as carboxypolymethylene, carboxmethyl cellulose,
cellulose acetate phthalate, or polyvin~lacetate.
The tablets m~y if desired consist of several
- 31 -
. ' :
~L~49S~l -
layers. Coated tablets may be produced by coatin~ cores ? ;
obtained in a si~lilar manner to the tablets~ with agents
commonly used for tablet coatings for example polyvinyl
pyrrolidone or shellac, gum arabic, talcum, titanium ~ -
dioxide or sugar. In order to obtain sustained release
or to avoid incompatibilities, the core may consist of
several layers too. The tablet-coat may also consist
of several layers in order to obtain sustained release, in
which case the Pxcipients mentioned above for tablets may
be used.
Syrups of the active ingredient according to the invention
or combinations of active ingredients may additionally
contain a sweetener, such as saccharin, cyclamate, glycerin
or sugar, and/or taste improving agents such as flavourings ;
e.g~ vanillin or orange extract. They may also contain ;
suspension agents or thickeners, such as sodium carboxymethyl
cellulose,wetting agents, such as for example condensation
products of fatty alcohols with ethylene oxide, or
preservatives, such as ~-hydroxybenzoates.
Injection solutions may, for example 9 be produced in the
conventional manner, such as by the addition of preservation
agents, such as ~-hydroxybenzoates~ or stabilizers, such
as Complexons. The solutions are then filled into
- 32 -
.
~ 49S~ILl
injection vials or ampoules.
Capsules containing one or several active ingredients may
be produced for example by mixing the active ingredients
with inert carriers, such as lactose or sorbitol 7 and
filling the mixture into gelatin capsules.
Suitable suppositories may, for example be produced by
mixing the active ingredient or active ingredient combina-
tions with the conventional carriers envisaged for this
purpose, such as neutral fats or polyethyleneglycol or
derivatives thereof.
Advantageously, the compositions may be formulated
as dosage units, each unit being adapted to supply a fixed
dose of active ingredient. Tablets, coated tablets,
capsules, suppositories and ampoules are examples of -
suitable dosage unit forms. Each dosage unit preferably
contains 0.5 to 100 mg. of the said active ingredient and
especially 1 to 20 mg of the said active ingredient.
The following examples illustrate the preparation
of compounds according to the invention, and also
pharmaceutlcal compositions containing such compounds as
active ingredients:-
`
- 33 -
.
~, .. ..
~0495~Ll
a) Reaction of optically active basic compounds with
optically active tetrahydrofurfuryl compounds. ~ -
~ 2-(D-tetrahydrofurfuryl)-[(lR, 5R, 9R)-2'-hydroxy-5,9-
dimethyl-6,7-benzomorphane]-methanesulfonate
2.17 g (0.01 mol) of (lR, 5R, 9R)~ 2'-hydroxy-5,9- ~ -
dimethyl-6,7-benzomorphane, 1.26 g of sodium hydrogen
carbonate and 1.82 g (0.011 mol) of D-(-)-tetrahydro-
furfuryl bromide are refluxed in a mixture of 15 ml of
dimethylformamide and 25 ml of tetrahydrofuran for 75
hours, with stirring. Subsequently, the reaction mixture
is evaporated in vacuo and the residue is shaken with 35
ml of chloroform and 35 ml of water. After separation
of the chloroform phase in a separating funnel, the a~-
ueous solution is extracted twice each time with 15 ml
of chloroform. The combined chloroform solutions are
washed with 30 ml of water, dried over sodium sulfate
- 34 -
~ ~ 4~ S~
and evaporated in vacuo~ The crude reaction product ob-
tained as the evaporation residue may be crystallized
either directly or, preferably, after purification by
column chromatography on aluminium oxide. The column
chromatography is effected by dissolving the crude pro-
duct in 25 ml of chloroform and the solution is applied
on a chromatography column with 50 g of aluminium oxide -
(activity step III, neutral) in chloroform. The column ~-
is eluted with a mixture of 99 parts by volume of chloro-
form and 1 part by volume of methanol and the eluate is
collected in fractions of 10 to 20 ml. After thin layer
chromatographic examination the fractions are combined
with the pure substance and evaporated in vacuo. The
residue is crystallized from a mixture of 10 ml of metha- -
nol and 6 ml of water. After standing overnight at
2C, the crystals are filtered off with suction
and washed with a little aqueous methanol. After drying
at 80C, 2.3 g (76.5% of theory) of crystallized base of
m.p. 197C are obtained, the melting point rising to
- 35 - ~
.
201C after recrystallization frorn aqueous methanol, but
rising no further after a second recrystallization. The
substance has a specific rotation of [a]D5= - 108.5
(c = l, methanol~
In order to convert the base into the methanesulfonate,
1.55 g (0.005 mol) of the crystallized base are dissolved
in 8 ml of ethanol and 0.47 g of methanesulfonic acid
are added to the solution which is mixed with absolute
ether (40 ml) until turbidity commences. After standing
for several days in a sealed vessel at 2C the salt is
separated ofE in the form of coarse crystals. The cry-
stals are filtered off with suction, washed with ethanol/
ether 1: 1 and then with ether and dried at 50C. 1.4 g
~70.5% of theory) of the title compound are obtained;
melting point 70C, decomposition. The hygroscopic sub-
stance does not alter its melting point after recrystal-
lization from ethanol/ether and drying at 50C in high
vacuum.
36
~,
.
~ ~ ~9 5
Example 2 (Process a)
(+)-2-(L-tetrahydrofurfuryl)-[lS,5S,9S)-2'-hydroxy-5,9-
dimethyl 6J7-benzomorphane]
In a similar manner to Example 1, 2.2 g (72.5% of theory) ;
of the title compound are obtained by starting from 2.17 g
(0.01 mol) of (lS,5S,9S)-(+)-2'-hydroxy 5,9-dimethyl-6,7-
benzomorphane, 1~26 g of sodium hydrogPn carbonate and
1 82 g (0.011 mol) of L-(+)-tetrahydrofurfuryl bromide.
The crystals obtained from the first crystallization
from aqueous methanol have a melting point of 199C, which
rises after recrystallization from aqueous methanol to
200C. The specific rotation of the substance [~]D
109.3 (c = 1; methanol.)
(-)-2~(L-tetrahydrofurfuryl)-[(lR,5R,9R)-2'-hydroxy-5,9-
dimethyl-6 J 7 benzomorphane]
In a similar manner to Example 1, 2.3 g (76.5% of theory)
of the title compound are obtained, starting from 2.17 g
(0.01 mo~ of (lR,5R,9R)-(-)-2'-hydroxy-5,9-dimethyl-6,7-
37 -
,~
~o~gs~ :
benzomorphane, 1.26 g of sodium hydrogen carbonate and
1082 g (0.011 mol) of L-(+)-tetrahydrofurfuryl bromide.
The crystals obtained from the first crystallization from
aqueous methanol, have a melting point of 133C, which
rises when recrystallized from aqueous methanol to 137C.
The substance has a specific rotation of [a]25 = -98.5
(c = 1, methanol).
~se3~
(+)-2-(D-tetrahydrofurfuryl~-[(lS,5S99S)-2'-hydroxy-5,9-
dimethyl-6,7-benzomorphane]
In a similar manner to Example 19 2.1 g (69.5% of theory)
of the title compound are obtained by starting from 2.17 g
(0.01 mol) of (lS,5S,9S)-(+)-2'-hydroxy-5,9-dimethyl-6,7-
benzomorphane, 1.26 g of sodium hydrogen carbonate and
1.82 g (0.011 mol) of D~ tetrahydrofur~uryl bromide.
The crystals obtained from the first crystallization from
aqueous methanol have a melting point of 133C, rising
after recrystallization to 137C. The substance has a
specific rotation of [a]D = + 98.2.
'
- 38 ~ .
; '
.. . .. . . . .
~ 0 4~ S~
b) Reaction of optically active basic compounds with
racemic tetrahydrofurfuryl derivatives.
Exam~le 5 (Process a)
2-(D-tetrahydrofurfuryl-[(lR95R,9R)-2'-hydroxy-5,9-
dimethyl-6,7-benzomorphane] and
~ 2(L-tetrahydrofurfuryl)-[(lR,5Ry9R)~2i~hydroxy-5,9-
dimethyl-6,7-benzomorphane]
21.7 g (0.1 mol) of (lR,5R,9R)()-2'-hydroxy-5,9 dimethyl-
6,7-benzomorphane, 12.6 g of sodium hydrogen carbonate,
18.2 g (0.11 mol) of (~)~tetrahydrofurfurylbromide and 2 g
of potassium iodide are heated to 100C in 200 ml of di
methyl-formamide for 18 hours, while stirring vigorously.
Subsequently9 the reaction mixture is cooled and mixed
with 400 ml of water while stirring over a period of 30
minutesO The crystals which precipitate are stirred at
room temperature for a further 2 hours. The precipitate
is then filtered off with suction, washed thoroughly with
several portions of water and after a final increase in
the suction dried at 80C, until weight constancy is
- 39 -
, .. .
. ~ .
`~--
i~49~
achieved. 21.0 g of a mixture of the diastereoisomeric
title compound is obtained. The mother liquor is stored.
In order to separate the diastereoisomers, the crystals
are recrystallized from 220 ml of methyl ethyl ketone.
After cooling overnight at 2C, the crystals are filtered
off with suction and washed with a little cool methyl
ethyl ketone. The mother liquor is stored and the crystals
are dried at 80C. 11.7 g of crystals of m.p. 197lC are
obtained, yielding after recrystallization from 270 ml of
methanol and 135 ml of water,10.6 g of pure (~)-2-(D-
tetrahydrofurfuryl)-[(lR,5R,9R)-2'-hydroxy-5,9-dimethyl-
6,7-benzomorphane] of m.p. 201C.
The second diastereoisomer is obtained from the dimethyl-
ormamide and the methyl ethyl ketone mother liquor:
the dimethylformamide mother liquor is evaporated in vacuo
and the residue crystallized from 50 ml of dimethylformam~
ide and 200 ml of water. After standing for two days
at room temperature, suction filtration, washing with
- 40 -
.
' ~ ,' , . : .
~ " ' ~ .` ' ' ' '
S~Ll
water, and drying at 80C, 4.1 g of the desired second dia-
stereoisomer is obtained in substantially pure form. A
further yield of the substance is isolated from the meth~1 -
ethyl ketone mother liquor. This is evaporated and the
residue crystallized from 30 ml of methyl ethyl ketone.
After standing overnight at room temperature the precipi
tate is filtered off with suction, whereby 4.4 g of cry-
stals are obtained from the methyl ethyl ketone mother
liquor 2. These crystals are dried at 80C. The crystals
are recrystallized from methyl ethyl ketone, whereby 1.4 g
of crys~als are obtained from the-methyl ethyl ketone
mother liquor 3. The latter consists of a mixture of the
two diasteroisomers in theratio of approximately 1 : 1 and
may again be subjected to the described separation. Mother
liquors 2 and 3 are combined and evaporated in vacuo. The
evaporation residue, like the second batch of crystals
~4 1 g) isolated from the dimethylformamide mother liquor,
consists of the second diastereoisomer. They are crystal-
lized together out of a mixture of toluene and benzene
. , , . , ,~: .
.. . ..
~ 9s~ :
(60 - 80C) in the volume ratio of 70 : 30 After standing
overnight at room temperature the crystals are filtered off
with suction and washed with benzene. After drying at 80C~
6.5 g of (-)~2-(L-tetrahydrofurfuryl)-[(lR,5R,9R)-2'-hy-
droxy-5,9-dimethyl-6,7-benzomorphane] of m.p. 137C are
obtained. From the evaporation residue of the mother -
liquor a further 2.7 g are obtained, by crystallization
from 50 ml of toluene/benzene. These crystals have
the same melting point. The total yield of the second
diastereoisomers amounts to 9.2 g
Exam~le 6 (Process a)
.
(-)-2-tetrahydrofurfuryl-2'-hydroxy-5,9,9-trimethyl-6,7
benzomorphane-methanesulfonate ;~
In a similar manner to Example 1, the title compound is
obtained starting from 1.16 g (0 005 mol) of (+)-2'-hy- -
droxy-5,9,9-trimethyl-6,7-benzomorphane and 0.91 g of D-
(-)-tetrahydrofurfuryl bromide, (melting point 182C) which
melting point does not change after recrystallization from
ethanol/ether~ This product is one of the two optically
.
.
~r~
~ 4gS~Ll
active diastereoisomers. The other may be isolated from
the mother-liquor.
c) Reaction of racemic basic compounds with racemic
tetrahydrofurfuryl derivatives.
(+)-2-tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzo-
morphane (racemic diastereoisomers I and II),
21 7 g (0.1 mol) of (~)-2'-hydroxy-5,9~-dimethyl-6,7-
benzomorphane, 13.7 g of sodium hydrogen carbonate9 19.9 g
(0.12 mol) of (+)-tetrahydrofurfurylbromide and 2 g of
potassium iodide are heated in 200 ml of dimethylformamide
to 100C for 18 hours, while stirring vigorously. Sub-
sequently the reaction mixture is cooled and, within 2
hours, mixed with 400 ml of water, filtered with suction
and the residue washed several times with water. After
increasing the suction and drying at 80C, 25.4 g of
crystals are obtained, which consist of the two racemic
diastereoisomers I and II. The mother-liquor is discarded.
- l.3
~ ~ ~9 51~
The racemic diastereoisomers I and II are separated in
the form of their hydrochlorides. The separation is
effected as follows: The mixture of diastereoisomers
is dissolved in 7.3 ml of conc. hydrochloric acid and 100
ml of ethanol. Crystallization starts immediately. After
standing overnight the crystals are filtered off with ~-
suction, washed with ethanol/ether 1:1 and then with
ether and dried, first in the air and then at 80C. 13~5 g
of the slightly impure hydrochloride of diastereoisomer
and the mother~liquor 1 are obtained. Recrystallization
from 350 ml of ethanol yields 8.1 g of pure substance of
m.p. 294~C and mother-liquor 2. Evaporation of mother ~ -
liquor 2 to 100 ml yields 2.6 g of crystals, after crystall-
zation, with a m.p. of 287 to 288C and mother liquor 3. The
latter is evaporated in vacuo together with mother liquor
1 and theresidue is crystallized from 50 ml of ethanol,
whereby 1.5 g of a subs~ance of m.p. 287 - 288C and
mother liquor 4 are obtained. The crystals of melting
point 287 to 288C are combined (4.1 g) and recrystallized
- 44
3i5~1
from 40 ml of ethanol. In so doing another 2.9 g of
pure hydrochloride of diastereoisomer I with m.p. 294C
and mother liquor 5 is obtained. Thus, the total yield
of pure substance of m.p. 294C amounts to 11.0 g.
The diastereoisomer II is isolated from mother liquors
3, 4 and 5 as follows: The mother liquors are evaporated
in vacuo and the residue is shaken with 75 ml of chloroform,
_
75 ml of water and 10 ml of conc. ammonia solution. After
separation of the chloroform phase in a separating funnel,
the aqueous phase is extracted once more with 25 ml of chl-
oroform. The combined chloroform extracts are washed with
water, dried over sodium sulfate and evaporated in vacuo.
The residue consists of the crude base of the second dias-
tereoisomer. The residue is crystallized from 100 ml of a
mixture of toluene and benzene (60-80C) in the volume ratio
70 ; 30. After standing overnight at room temperature the
crystals are filtered off with suction, washed with a little
cold toluene/benzene, then with benzene and dried at 80C.
10.6 g of pure diastereoisomer II of m.p. 166C is obtained.
- 45 ~
The evaporated mother liquor yields a residue of 3.5 g,
consisting of a mixture of the two diastereoisomers~ which
may again be used in the described separation.
Thus, according to Example 7,11~0 g of (~)-2-tetrahydro-
furfuryl-2 7 -hydroxy-5,9a-dimethyl~6,7-benzomorphane hydro-
chloride (diastereoisomer I) and 10.6 g of (+)-2-tetra- :
hydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane
(diastereoisomer II) are obtained.
By resolution of the racemates the compounds described in
Examples 1 and 2 may be obtained as the optically active
isomers from diastereoisomer I. Similarly the compounds
described in Example 3 and 4 may be obtained as optically
active isomers from diastereoisomer II.
Example 8 (Process a) - -
:-
(+)-2-tetrahydrofurfuryl-2'-hydroxy-5,ga-dimethyl-6,7-
ben~omorphane (racemic diastereoisomer I).
2.18 g (0.01 mol) of 2'-hydroxy-5,9a-dimethyl-6,7-benzo-
morphane, 1.26 g of sodium hydrogen carbonate and 2.82 g
:
. , ~ .. .
.. . . . . ~ : , .
1 ~ ~9 5~1
(0.011 mol) of ~-toluene-sulfonic acid tetrahydrofurfuryl
ester are refluxed in a mixture of 20 ml of dimethylfor-
mamide and 25 ml of tetrahydrofuran for 6 hours, while
stirring. The reaction mixture is then filtered when
still warm and the filtrate evaporated in vacuo at approxi-
mately 50C, thus eliminating the tetrahydrofuran. After
the addition of 40 ml of water, the mixture of diastereoiso-
mers described in Example 7 crystallizes out, the latter
being separated in the manner indicated therein, yielding
1.0 g of hyclrochloride of diastereoisomer I, m.p. 294C.
For conversion into the base, the hydrochloride is diss-
olved in 10 ml of water and the solution made ammoniacal
by the dropwise addition of 1 N ammonia solution w~ile
stirring. In so doing the base precipitates out. After stand-
ing overnight at room temperature, the precipitate is filter-
ed off with suction, washed with water and after an increase
in suction recrystallized from 20 ml of methanol and 7 ml -
of water. 0.75 g of substance with a melting point of
175 - 176C are ob~ained~ which melting point remains
- 47 - -~
5~1 '
unchanged after recrystallization from aqueous methanol.
~ ,,
(+)-tetrahydrofurfuryl-2'-hydroxy-5,9,9-trimethyl-6,7-ben-
zomorphane methanesulfonate (racemic diastereoisomer I)
In a similar manner to Example 1, the title compound is
obtained starting from 1.16 g (0.005 mol) of (+)-2'-
hydroxy-5,9,9,-trimethyl-6,7-benzomorphane and 0.91 g
(0.0055 mol) of (+)-tetrahydrofurfuryl bromide, m.p. 207-
210C. The melting point rises after recrystallization
from ethanol/ether to 210C. The product is one of the
two racemic diastereoisomers. The second may be isolated
from the mother liquors.
~L~ .
(+)-2-tetrahydrofurfuryl-2'~hydroxy-5-methyl-9a-ethyl-6,7-
benzomorphane
2.31 g (0.01 mol) of (+)~2'~hydroxy-5-methyl-9~-ethyl-6,7-
benzomorphane, 1.3 g of sodium hydrogen carbonate, 1.97 g
(0.012 mol) of (~)-tetrahydrofurfuryl bromide and 0.2 g of
,: . . . :, . , : . . ~ , , .
~ 4~ 5~1
sodium iodide are refluxed in a mixture of 15 ml of dime-
thylformamide and 25 ml of tetrahydrofuran for 60 hours,
while stirring. The reaction product is isolated as in-
dicated in Example l, purified by chromatography on 75 g
of aluminium oxide and crystallized from aqueous methanol.
Yield 1.2 g. After recrystallization from 20 ml of metha-
nol and 5 ml of water the melting point of 171C does not
change. The crystallized substance thus obtained is one
of the two racemic diastereoisomers formed during the
reaction. The other may be isolated from the mother liq-
uors.
' ' .:
''' '
(+)-2-tetrahydrofurfuryl~2'-hydroxy~5-ethyl-9~-methyl-6,7-
benzomorphane
1.3 g of the title compound of melting point 170C is -~
obtained starting from 2.31 g (0.01 mol) of (+)-2'-hydroxy~
S-ethyl-9a-methyl-6,7-benzomorphane and 1.97 g (0.012 mol)
of (+)-tetrahydrofurfuryl bromide according to Example 10.
The melting point does not change when recrystallized from
'~
~ 49
.
- , ' ~ . . ' , :
~9~
30 ml of methanol and 10 ml of water. The crystallized
substance thus obtained is one of the two racemic stereo-
isomers formed during the reaction. The other may be
isolated from the mother liquors.
_a~e~__12 (Process a)
(+)-2-tetrahydrofurfuryl-2'-hydroxy-5,9~-diethyl-6,7-
benzomorphane hydrochloride.
A reaction product is obtained starting from 2.45 g (0.01
mol) of (+)-2'-hydroxy-5,9~-diethyl-6,7-benzomorphane and
1.97 g (0.012 mol) of (~)-tetrahydrofurfurylbromide,
which product is purified by chromatography on aluminium
oxide, according to Example 10 The base thus obtained
is dissolved in 10 ml of absolute ethanol and, after
acidification, is mixed with 2 N ethanolic HCl and abso-
lute ether until turbidity is achieved. The hydrochloride
crystalliæes out, and is filtered off with suction after
standing overnight. The crystals are washed with ethanol/
ether 1:1, then with ether and dried at 80C. 1.0 g of the
title compound is obtained having a melting point 239C,
which does not change after recrystallization from ethanol/
ether. The substance thus obtained is the hydrochloride
- 50
-
~ 0 49 S ~
of one of the racemic diastereoisomers formed during the
reaction. The other can be isolated from the mother
liquor.
~,}~
(+)-2-tetrahydrofurfuryl-2~hydroxy~5~methyl-6 7 7-benzomor~ ~-
phane-methanesulfonate
In a similar manner to Example 1, 2.1 g of the title
compound are obtained by starting from 2.03 g (0.01 mol)
of (+)-2'-hydroxy-5-methyl-6,7-benzomorphane and 1.97 g
(0.012 mol) of (+)-tetrahydrofurfuryl bromide. The
product has a melting point of 171 to 172C, The melting
point does not change after recrystallization from 5 ml
of ethanol and diethyl ether. The substance thus obtained
is one of the two racemic diastereoisomers formed during ;~
t~ reaction. The other can be isolated from the mother ~-~
liquor,
~t~ . ,
(+)-2-tetrahydrofurfuryl~2'-hydroxy-5-ethyl-6,7-benzomor-
phane
- 51
'
~ . . ., ~ .
... . ..
16~495~
In a similar manner to Example 10, 2.0 g of the title
compound are obtained by starting from 2.17 g (0.01 mol)
of (+)-2'-hydroxy-5-ethyl-6,7-benzomorphane and 1 97 g
(0.012 mol) of (+)-tetrahydrofurfuryl bromide, the melt-
ing point of which is 150 to 151C, and does not change
when recrystallized from 40 ml of acetone and 30 ml of
water. Ihe substance thus obtained is one of the two
racemic diastereoisomers formed during the reaction. The
other may be isolated from the mother liquor.
Example 15 (Process a) :-
(+)-2-tetrahydrofurfuryl~2'-hydroxy-5-n-propyl-6,7-benzo-
morphane
In a similar manner to Example 10, 2.1 g of the title
compound are obtained by starting from 2.31 g (0.01 mol)
of ~+)-2'-hydroxy-5-n-propyl-6,7-benzomorphane and 1.97 g
(0,012 mol) of (+)~tetrahy~rofuryl bromide, the melting
point of which is 152C and does not change after recry-
stallization from 30 ml of methanol and 40 ml of water~
The substance thus obtained is one of the two racemic
~. '
- 52
- -; , ,
s~
diastereoisomers formed during the reaction. The other
can be isolated from the mother liquor
Exam~l 6 ~
(+)-2-tetrahydrofurfuryl-2'-hydroxy-599~-dimethyl-6,7-
benzomorphane (racemic diastereoisomers I and II)
21 7 g (0.1 mol) of (~)-2~-hydroxy-5,9~-dimethyl-6,7-
benzomorphane are dissolved in 400 ml of methanol while
heating and the solution is mixed at room temperature ,
while stirring vigorously, with 25 g of potassium carbonate
dissolved in 40 ml of water. In so doing, a finely
crystalline mixture of the base and the carbonate preci~
pitates out. While the vigorous stirring is continued,
22.2 g (0.165 mol) of tetrahydrofuran-2-carbonic acid
chloride are added drop~ise to the suspension over a period
o 30 minutes, while stirring is continued for one hour.
The mixture is then evaporated in vacuo and the residue
is shaken with 150 mI of chloroform and 100 ml of water.
The aqueous phase is extracted after separation from the
- 53
- . ..
', ' ' ~ " . '.
51~
chloroform layer in a separating funnel once more with 50
ml of chloroform. The combined chloroform extracts are
washed successively with 100 ml of 1 N HCl and 100 ml of
water, dried over sodium sulfate and evaporated in vacuo
after the addition of 50 ml of toluene. The residue con-
sists of 2-(tetrahydro-2-furoyl)-2'-hydroxy-5,9a-dimethyl-
6,7-benzomorphane, which is used for the following reduc-
tion:
The evaporation residue is dissolved in 250 ml of absolute
tetrahydrofuran and the ~lution added dropwise over a
period of 20 minutes to a suspension of 12 g of lithium
aluminium hydride in 150 ml of absolute tetrahydrofuran
and cooled with ice, while Rtirring. Subsequently, the
ice-bath is removed and stirring is continued for 1 hour
at room temperature, the product is then refluxed for 2 ;
hours. The refluxed mixture is then cooled and, while
stirring and ice-cooling, mixed dropwise with 50 ml of
water. 1200 ml of saturated diammonium tartrate solution
is then added, shaken in the separating funnel and, when
54
s~ :
well settled the(upper) tetrahydrofuran phase is separated
from the heavy aqueous layer. The tetrahydrofuran solution
is evaporated in vacuo, the aqueous solution is extracted
with 100 ml of chloroform. The evaporation residue of the
tetrahydrofuran solution is dissolved with the chloroform
extract, the solution is washed with water, dried with
sodium sulfate and evaporated in vacuo. A crude mixture
of the diastereoisomers is obtained, which is separated
using 8 ml of conc. HCl and 100 ml of ethanol via the hydro-
chloride 9 as dèscribed in Example 6. The separation
yields 11.3 g of pure hydrochloride of the diastereoiso-
mer I of m p. 294C and 9.3 g of the diastereoisomere II
(base) with melting point 166C.
Example l? (Proce
~ ,
(-)-2-(D-tetrahydrofurfuryl)-glR,5R99R)-2'-hydroxy-5,~-
diméthyl-6,7-benzomorphane~ and
(-)-2-(L~tetrahydrofurfuryl-[(lR,5R~9R)~2'-hydroxy-5,9-
dimethyl-6 9 7~benzomorphane]
To a suspension of 8.7 g (0.04 mol) of (lR, 5R, 4R)~
... . ...
- 55
.'',''"
s~ :
2'-hydroxy-5,9-dimethyl-6,7-benzornorphane in 87 ml of
absolute methylene chloride and 16 ml of triethylamine is
added dropwise over a period of 15 minutes, at room temp-
erature~ while stirring, a so~ution of ll.9 g (0.88 mol)
of tetrahydrofuran-2-carboxylic acid chloride in 40 ml of
absolute methylene chloride using a reflux-cooler. The
reaction mixture is then refluxed for a further 2 hours.
Afterwards, the mixture is cooled, washed twice each time
with 30 ml of water, dried with sodium sulfate and eva-
porated in vacuo. The residue consists of the crude 2-
(tetrahydro-2-furoyl)-2'-(tetrahydro-2-furoyloxy)-5,9~
dimethyl-6,7-benzomorphane, which is used for the following
reduction:
In a similar manner to Example 16, the evaporation residue
is reduced using 5.0 g of lithium alumini~m hydride and
the reduction product is isolated from the tetrahydro-
furan phase and the chloroform extract of the diammonium
tartrate solution, as described. The product consists of
- 56
., . ~ .
.. . .. .
~ 95i~L
the crude mixture of the title compounds, which are
separated from each other in a similar ~anner to Example
5 and obtained in pure form. 4.8 g of (-)-2-(D-tetrahy-
drofurfuryl)~[(lR,SR,9R)~2'-hydroxy 599-dimethyl-6,7-
benzomorphane] of melting point 201C and 3.4 g of (-)-
2-(L-tetrahydrofururyl)-[(lR,5R,9R)-2'-hydroxy-5 9 9-di-
methyl-6,7-benzomorphane] of melting point 137C are
obtained
Example 18~ Process b)
(-)-2-(D-tetrahydrofurfuryl)-~lR,5R,9R)-2'-hydroxy-5,9-
dimethyl-6,7-benzomorphane~ and
(-)-2-(L-tetrahydrofurfuryl)-[(lR,5R,9R)-2'-hydroxy-5,9- -
dimethyl-6~7-benzomorphane]
In a similar manner to Example 16, 4.34 g (0.02 mol) of --
(lR, 5R, 9R)~ 2'~hydroxy-5,9~dimethyl-6,7-benzoMor-
.. . .
phane are co~verted into the corresponding 2~(tetrahydro-
2-furoyl)-derivative. 8.3 g of crude product are obtained
as evaporation residue, which is thionated as follows to
yield the corresponding 2-(te~rahydro-2-thiofuroyl)-
.:
- 57
, ~, . . . .. . . .
~o~
derivative:
The residue is disso]ved in 100 ml of absolute pyridine
and the solution is refluxed with 2.6 g of phosphorus
pentasulfide for 3 hours. Subsequently, the solution is -
evaporated in vacuo and the residue shaken with lOO ml of
methylene chloride and 100 ml of water After separation
in a separating funnel, the aqueous phase is extracted
once more with 50 ml of methylene chloride. The combined
methylene chloride solutions are washed successively in
the presence of ice, with 30 ml of 2 N HCl and three times,
each time with 30 ml of water. After drying with sodium
sulfate and evaporation in vacuo a residue residue9 con-
sisting of the crude 2-(tetrahydro~2-thiofur~yl) derivative
(5 2 g).
This is further reacted in the next reaction step.
In a similar manner to Example 16 9 the evaporation residue
of the methylene chloride solution is reduced using 1.5 g
of lithium aluminium hydride~ me reaction product is
purified by column chromatography on aluminiumoxide, as
- 58
~ llJ 495~
described in Example 1. The purif;ed, but not yet separ-
ated, mixture of the two title compounds is thus obtained.
Separation is effected according to Example 5 and yields
006 g of (~)-2-(D-tetrahydrofurfuryl)- and 0~5 g of (-)-2-
(L-tetrahydrofurfuryly-[(lR,5R,9R)-2'-hydroxy-5,9-dimethyl-
6,7-benzomorphane with the melting points 201 and 137C
respectively.
,
, .
~ 2 (D-tetrahydrofurfuryl)-[(lR,5R,9R)-2'-hydroxy-5,9-
dimethyl-6,7-benzomorphane~ and
(-)-2-(L-tetrahydrofurfuryl-[(lR,5R,9R)-2'-hydroxy-5,9-
dimethyl-6,7-benzomorphane]
4.34 g (0.02 mol) of (lR, 5R, 9R)-(-)-2~-hydroxy-5,9-di-
methyl-6,7-benzomorphane are converted into the 2-(tetra- -
hydro-2-thiofuroyl)-derivative, in a similar manner to
Example 18. The starting material is refluxed under
anhydrous conditions in 120 ml of absolute acetone with
6.3g of methyl iodide for 2 hours. The reaction product
is precipitated with 600 ml of absolute ether and the super- .
- 59
.. :, .
: :; , , , ~ - ,
~9~1
natant solution decanted after clearing. In this manner ~ -
the methiodide of the 2-(tetrahydro-2-thiofuroyl) compound
is obtained, which is reduced with sodium borohydride.
For this purpose the precipitation product is added to
40 ml of absolute ethanol and 2.3 g of finely pulverized
sodium borohydride in 5 portions, while stirring and over
a period of 5 minutes. The temperature rises from 23
to 53C in the first 15 minutes. After a total reaction
time of 1 hour , the reaction mixture is cooled and mixed
dropwise with 100 ml of 2 N HCl. The ~reaction mixture is
refluxed for 30 minutes. Afterwards, it is cooled and
made ammoniacal with concentrated ammonia and extracted
with 100 ml of chloroform. After separation in a separ-
ating funnel, it is shaken once more with 50 ml of chloro-
form and the combined chloroform extracts are washed twice
with water, dried with sodium sulfate and evaporated _
vacuo. As described in Example 1, the residue is purified
on aluminium oxide, whereby the purified but not yet sep-
arated mixture of the two title compounds is obtained.
~ 60
s~
The separation, carried out according to Example 5, yields
0.4 g (-)-(D-tetrahydrofurfuryl)and 0.25 g of (-)-(L-tetra-
hydrofurfuryl)-[(lR,5R,9R)- 2'-hydroxy-5,9-dimethyl-6,7-
b~nzomorphane with melting points of 201 and 137C
respectively.
Ex~ple 20 (Process e)
.. . .
( )-2-tetrahydrofurfuryl-2'-hydroxy-5,9~-dimethy1-6,7-ben-
zomorphane (racemic diastereoisomer I and II) -
a) l-tetrahydrofurfuryl-2-(p-methoxybenzyl)-3,4-dimethyl-
4~hydroxy-piperdine (mixture of isomers)
2409 g (0.1 mol) of 2~ methoxybenzyl)-3,4-dimethyl-4-hy-
droxy-piperidine are st~rred in 200 ml of dimethylformamide
in the presence of 12.6 g of sodium hydrogen carbonate
for 24 hours at 100C with 19.7 g (0.12 mol) of tetrahydro-
furfuryl bromide. Subsequently, the reaction mixture is
evaporated in vacuo and the residue shaken with 150 ml of
chloroform and 100 ml of water. After separation by means
o a s~parating funnel, the aqueous phase is extracted once
~nore with 50 ml of chloroform. The combined chloroform
_ 61
1ID4~35~a
extracts are washed with water, dried with sodium sulfate
and evaporated in vacuo. According to the method des-
__
cribed in Example 1, the residue is purified by column
chromatography on aluminium oxide (700 g, activity step
III, neutral) using chloroform as the mobile phase. After
evaporation of the eluate comprising the pure substance,
a residue of 16 g is obtained, which is further reacted
in the following step.
b) Cyclization to yield the title compounds
16 g of 1-tetrahydrofurfuryl-2-(p-methoxybenzyl-3,4-dimeth-
yl-4-hydroxy-piperidine (evaporation residue from the
preceding reaction step) are stirred with 80g of
crystallized phosphoric acid under an atmosphere of ni-
trogen at 130C for 26 hours. The reaction mixture is
then diluted with 85 ml of water and refluxed for 5 hours.
After cooling the refluxed products are mixed with 150 ml
of benzene, 150 ml of n-butanol and 165 ml conc. ammonia
and shaken thoroughly. The organic layer is separated out
- 62
~ 95~
by means of a separation funnel, the aqueous phase is
shaken twice with benzene/n-butanol. The combined organic ;~
phases are washed with water 3 times, dried with sodium
sulfate and evaporated n vacuo. The residue (10 g) is
dissolved in 50 ml of chloroform and the solution applied -
to an aluminium oxide column for chromatography. 200 g
of aluminium oxide (activity step III, neutral) are used
for this purpose and further processing is effeeted as
described in Example 1. The fractions of the pure sub-
stance determined by chromatography (thin-layer) are com-
bined and evaporated in vacuo. Thus 7 4O0 g of residue
are obtained consisting of a mixture of the two stereo-
isomers I and II, the mixture being separated into the
pure components, according to Example 5. The separation
yields the stereoisomers in the form of their hydrochlor-
ide, with a melting point of 294C, yielding 1.9 g and
stereoisomer II as base, melting point 166C, yielding
1.3 g.
- 63
,
111 9~S~l
~'~
(+)~2-(tetrahydrofurfuryl-2'-hydroxy-5,9~-dimethyl-6,7-
benzomorphane (racemic diastereoisomer I and II)
a) (+)-2-(2-oxo-4-ethoxycarbonyl-butyl)-2'-hydroxy-5,
9a-dimethyl-6,7-benzomorphane hydrochloride.
10.85 g (0.05 mol) of (+)-2'-hydroxy-5,9a-dimethyl-6,7-
benzomorphane, 4.6 g of sodium hydrogen carbonate and 12.3 g
(0.055 mol) of 5-bromo-ethyl levulinate are refluxed in
50 ml of dimethylformamide and 125 ml of tetrahydrofuran,
while stirring for 2 hours. Subsequently9 the reaction
mixture is evaporated in vacuo and the residue is shaken
with 250 ml of chloroform and 100 ml of water. The aqueous
phase separated out by means of a separating funnel is
extracted once more from chloroform (50 ml), the combined
chloroform solutions are washed with water, dried with
sodium sulfate and evaporated in vacuo. The residue is
dissolved with 75 ml of 2 N ethanolic HCl and the solution
is mixed with absolute ether until turbidity begins. The
title compound crystallizes out. After standing overnight
- 64
~1~4~5~
the crystals are filtered off with suction at 2C and
washed with ethanol/ether l : l and thereupon with ether.
Afterwards, the crystals are dried first in air, then
at 80C. 18.2 g (92% of theory) of the title compound with
a melting point of 212 to 215C is obtained. A sample,
recrystallized from ethanol/ether, melts at 214 to 216C.
When recrystallizing further the melting point does not
change.
b) (+)-2~(2,5-dihydroxy-n-pentyl)-2-hydroxy-5,9a-dimethyl-
6.7-benzomorphane (mixture of stereoisomers) -
19.8 g (0.05 mol) of (+)-2-(2-oxo-4-ethoxycarbonal-butyl)- `
2'-hydroxy-5 9 9a-dimethyl-6,7-benzomorphane hydrochloride
are converted by shaking with lO0 ml of chloroform, 100 ml
of water and 7 ml of conc. ammonia ~to the corresponding
base, the latter being dissolved in the chloroform phase
After separation of the chloroform phase, the aqueous
phase is extracted once more with 25 ml of chloroform, the
chloroform extracts are combined, washed with water, dried
over sodium sulfate and evaporated in vacuo. The residue
- 65 -
~ 9 S~
is reduced with lithium aluminium hydride. To this
product is added dropwise the solution of the evaporation
residue in 100 ml of absolute tetrahydrofuran9 while
stirring and ice-cooling, over the period of an hour,
which is also added to a suspension of 2.9 g of lithium
aluminium hydride in 250 ml of absolute tetrahydrofuran.
Stirring is then continued for another hour at room temp-
erature and finally the mixture is refluxed for 3 hours.
Subsequently, the reaction mixture is allowed to cool and,
while stirring and ice-cooling, mixed dropwise with 10 ml of
water and then with 290 ml of saturated diammonium tar-
trate solution. After shaking well, the mixture is
separated by means of a separating funnel. The(upper)
tetrahydrofuran phase is evaporated in vacuo, the aqueous
phase is extracted with 100 ml of chloroform each time.
The combined chloroform extracts are taken up.with the
evaporation residue of the tetrahydrofuran phase and the
solution is washed twice with water. After drying with
- 66
:
1049511
sodium sulfate and evaporating in vacuo, the crude reduction
product is obtained (17.5 g).
This is purified by chromatography on aluminium oxide.
350 g of aluminium oxide (activity step III, neutral)
are used and the purification is effected as described in
Example 1. The product is first eluted with chloroform,
then with a mixture of chloroform and methanol in the volume
ratio of 99 : 1, whereby fractions of 25 ml are collected.
After thin-layer chromatographic Pxamination, the fractions ~-
are combined with the pure main product and evaporated in
vacuo. A residue remains of the main reduction product,
. .
consisting oE a mixture of stereoisomers.
c) (+)-2-tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-
benzomorphane (racemic diastereoisomers I and II)
The evaporation residue of the preceding reaction step
(17,5 g) is boiled under reflux and in a water-sep~rator
with 17.5 g of ~-toluenesulfonic acid in 800 ml of xylene
for 45 minutes. Subsequently, the reaction ~ixture is
evaporated in vacuo and the residue is shaken with 100 ml
- 67
. .
. :: , - . ; - ' '
.
- . , . .
g51~L
of chloroform, 50 ml of water and conc. ammonia (10 ml).
After separation by means of a separating f~mnel, the
mixture is extracted once more ~ith 25 ml of chloroform.
The combined chloroform extracts are washed twice, each
time with 30 ml of water, dried with sodium sulfate and
evaporated in vacuo. The evaporation residue is purified
by chromatography on 500 g of alumini~m oxide (activity
step III, neutral), using the method described in Example
1. The residue is eluted with chloroform/methanol, first
with a volume ratio of 99:1, for separation of the faster f
running impurities, then with a volume ratio of 95 : 5.
The fractions comprising the pure reaction products, are
purified and ev~porated in vacuo. 12 g of residue remain
containing the remaining solvents~ Separation of the two
diastereoisomers is carried out as described in Example 7.
In so doing the hydrochIoride of the diastereoisomer I is
obtained (2.4 g) as well as the diastereoisomer II in the
form of its base (2.2 g). After recrystallization the
melting points of 284C and 161 respectively rise to
." .. .
- 68 - -
.:': ~ .
,. .... . . . . . . .
iLil)4~5~1LSL
294 and 166C respectively.
~Z " .
(+)~2-tetrahydrofurfuryl-2'~hydroxy-5,9a-dimethyl-6,7-
benzomorphane (racemic diastereoisomers I and II)
a) (~)2-tetrahydrofurfuryl-2'-benzoyloxy-5,9a-dimethyl-
6 7 7-benzomorphane (mixture of diastereoisomers)
In a similar manner to Example 8, 3.21 g (0.01 mol) of 2'-
benzoyloxy 5,9a-dimethyl-6,7-benzomorphane are alkylated
in the presence of sodium hydrogen carbonate in dimethyl-
formamide/tetrahydrofuran with 2 82 g of p-toluenesulfonic
acid tetrahydrofuryl ester. Subsequently, the reaction
mixture is evaporated in vacuo and the residue is shaken
with 50 ml of chloroform and 50 ml of water. After sep-
aration by means of a separating funnel, the aqueous
phase is extracted once more with 25 ml of chloroform. The
combined chloroform extracts are, after washing with water,
dried with sodium sulfate and evaporated in vacuo. A&
residue is obtained A mixture of the two racemic, diastereo
isomeric (+)-2-tetrahydro-furfuryl-2'-benzoyloxy-5,9a-di-
- 69 ~
.
; . . . .. .
. ~
. .
: ~ . . : . . . .
104g511
methyl~6,7-benzomorphanes are obtained as a residue.
b) (~)-2-tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-
6,7-ben~omorphane (racemic diastereoisomers I and II)
The evaporated residue of the preceding synthesis step
is dissolved in 75 ml of methanol and the solution is
refluxed after the addition of 20 ml of 2 N NaOH for 15
minutes. The reaction mixture is then acidified with 25 ml
of 2 N HCl and evaporated in vacuo. The residue is shaken
with 50 ml of chloroform, 50 ml of water and 2 ml of conc.
ammonia. After separation by means of a separating funnel,
the aqueous solution is extracted once more with 25 ml
of chloroform. The combined chloroform extracts are
washed with water, dried with sodium sulfate and evaporated
in vacuo. The residue consists of the two racemic diaster-
:, . ..
eoisomers I and II, which are separated by crystallization
of the hydrochlorides, in a similar manner to Example 7. -
Thus, the hydrochloride of the diastereoisomer I is ob-
tained in a yield of 0.7 g, with a melting point of 294C
and the diastereoisomer II is obtained in a yield of
'
- 70
~ -, , ",
.
~ ~9
0.4 g with a melting point of 166C.
Example _
(+)-2-tetrahydrofurfuryl 2'--hydroxy-5,9a-dimethyl-6,7-
benzomorphane (racemic diastereoisomer I)
2.0 g (000062 mol) of (~)-tetrahydrofurfuryl-2'-methoxy-
S,9a-dimethyl-6,7-benzomorphane (0-methyl derivative of
title compound) are heated to 210C with 2 g of finely
pulverized potassium hydroxide in 20 ml of diethylene
glycol for 4 hours. After cooling, the reaction mixture
is diluted with 100 ml of water, acidified with conc. HCl,
made ammoniacal with conc. ammonia and shaken with 50 ml
of chloroform. The aqueous phase separated by means of a
separating funnel is twice extracted with chloroform each
time with 25 ml of chloroform. The three chloroform ex-
tracts are combined, washed with water, dried with æodium
sulfate and evaporated in vacuo . The residue yields9 after
crystallization from aqueous methanol, 1.7 g (89% of theory)
of the title compound with a m.p. of 173 to 175C, rising
after recrystallization from aqueous methanol to 176C.
- 71
. .
.
95~L
Example 24 (Process i)
~ tetrahydrofurfuryl~2'~hydroxy-5,9a-dimethyl-6,7-benzo-
morphane (racemic diastereoisomer I)
2.0 g (0.0062 mol) of (+)-2-tetrahydrofurfuryl-2'-methoxy-
5,9a-dimethyl-6,7-benzomorphane (0-methyl-derivative of
title compound) are he~ted to 190C with 20 g of anhydrous
pyridine hydrochloride for 30 minutes. After cooling
the melt is mixed with 20 ml of water and 12.5 g of sodium
carbonate and the pyridine is distilled off with steam.
The residue is shaken with 50 ml of chloroform ~nd the
aqueous phase separated by means of a separating funnel ;
and extracted once more with 25 ml of chloroform. The
combined chloroform extracts are washed with water, dried
with sodium sulfate and evaporated i vacuo. The residue
is crystallized from aqueous methanol. 0.9 g of the title
compound is obtained, which corresponds to a yields of 47%
: . .
of theory. The substance melts at 171 - 174C and after
recrystallization from aqueous methanol at 176C.
':'
- 72 -
:
~ ' .
. - - . . ~. . . . : . : ... .
~ 5
Example 25 _Process j)
~ 2-(D-tetrahydrofurfuryl-[(lR,SR,9R)-2'-acetoxy5,9-
dimethyl-6,8-benzomorphane]
3.0 g (0.01 mol) of (~ 2-(D-tetrahydrofurfuryl-[(lR,5R,
9R)-2'-hydroxy-5,9-dimethyl-6,7-benzomorphane] are heated
on a boiling water-bath with 25 ml of acetic acid anhydride
for 30 minutes. Subsequently, the reaction mixture is
evaporated in vacuo and the residue st~rred for several
minutes with 100 g of ice and 100 ml of water. After
addition of 100 ml of ether, the mixture is made just
about ammoniacal with 2 N ammonia, while stirring is con~
tinued. The ether phase is separated off and the aqueous
solution once more extracted with 50 ml of ether. The
combined extracts are washed with water, dried well with
sodium sulfate and evaporated in vacuo. There remains the
title compound in the form of a yellowish syrup. The sub-
stance is thin-layer chromatographically pure and possesses
73 -
,. . '
- ...................... ~ . : ~
,.;
s~
an Rf-value of 0.5, compared to the Rf-Yalue of 0.25
of the starting substance (DC silica gel, chloroform/
methanol/ conc. ammonia 90 : 10 : 0.5).
Example 26 (Process 1)
(+)-2~terahydrofur uryl-2'-methoxy-5,9a-dimethyl-6,7-
benzomorphane (0-methyl derivative of the diastereoiso- :
mer I from Example 7)
3.37 g (0.01 mol) of (+)-2~tetrahydrofurfuryl-2'-hydroxy-
5~9~dimethyl-5,7-benzomorphane hydrochloride (diastereo- :
isomer I from Example 7) and 1.9 g (0.011 mol) of phenylo ~ :
trimethyl-ammonium chloride are dissolved together in 100
ml of methanol and the solution is mixed while stirring with
1.08 g (0 02 mol) of sodium methoxide. In so doing, sodium
'~ " '.
.
- 74 -
~ . . . .
.:, . , . . , . ,.: , , -
' ' ~, ' ' ~ ~. '
5~
ammonium chloride are dissolved together in 100 ml of
methanol and the solution is mixed while stirring with 1 08 g
(0.02 mol) of sodium methoxide. In so doing, sodium
chloride precipitates, which is filtered off with suction
after 2 hours' stirring. The filtrate is evaporated, the
residue dissolved with dimethylformamide and the solution
evaporated again. Then fresh dimethylformamide (30 ml)
is added to the reaction mixture and refluxed for 2 hours.
After cooling the reaction mixture is evaporated and the
residue shaken in a separating funnel with 50 ml of 2N NaOH
and 50 ml of chloroform. After separation of the phases,
the aqueous solution is extracted twice, each time with 50 ml
of chloroform. The combined extracts are washed with water,
dried in sodium sulfate and evaporated in vacuo. The
residue is purified by chromatography on 200 g of silica gel,
using the mobile phase chloroform/methanol/conc. ammonia
in the volume ratio of 90 : 10 : 0.5. The evaporation
residue for this purpose is dissolved in 20 ml of t~e mo~ile
phase and the solution is applied on a silica gel column,
~hich was prepared using the mentioned mobile phase, for
chromatography. It is eluted and the eluate is retained
in fractions of 25 ml. After examination by thin-layer
- 75 -
' - ' -~ .
5~ 1 ,
chromatogram, the fractions are combined with the pure
substance and evaporated in vacuoO The residue is
,
dissolved in a little ethanol and the solution acidified
with ethanolic HCl and mixed with ether until turbidity
begins. The hydrochloride crystallizes ou~, and is filtered
off with suction after standing overnight at 2C, washed
with ethanol/ether l:l, then washed with ether and dried at
80C. 1.5 g of the title compound are obtained with a
melting pount of 207 to 208C, which does not change after .
recrystallization from ethanol/ether.
:' .
- 76 -
. '''~.'""'.
. :. . : ,,- ,~. ,
~1951~ , ,
Pharmaceutical Composition Examples
Example A: Tablets
(-)-2-(D-tetrahydrofurfuryl)-[~R,5R,9R)-
2l-hydroxy-5,9~dimethyl-6,7-benzomorphane3-
methanesulfonate 20.0 mg
lactose 120.0 mg
corn starch 50.0 mg
colloidal silicic acid 2.0 mg
soluble starch 5.0 mg
magnesium stearate 3.0 mg
200.0 mg
Production:
The active ingredient is mixed with part of the excipients
and granulated with a solution of the soluble starch in
water. After drying the granulate the remaining excipients
are added to the granulate and the mixture pressed into
tablets.
~xam~ ated Tablets
(-)-2-(D-tetrahydrofurfuryl)-[(lR,5R,9Rj-
2'-hydroxy-5,9 dimethyl-6,7-benzomorphane]-
methanesulfonate 15.0 mg
lactose 100.0 mg
corn starch 95.0 mg
- 77 -
~ 51 ~
colloldal silicic acid 2.0 mg
soluble starch 5.0 mg
magnesium stearate 3.0 m~ -
220.0 mg
Production: ;
.
As described in Example A, the active ingredient and the
excipients are pressed into tablet cores, the cores being
coated, as u9ual9 with sugar9 talcum and gum arabic.
Example C: Su~positories
~ 2-(L-tetrahydrofurfuryl)-[(lR,SR,9R)-
2'-hydroxy-5,9-dimethyl-6,7-benzomorphane] lO.0 mg
lactose 150.0 mg
suppository mass q.s.ad 1.7 g
Production:
The active ingredient and lactose are mixed together and
the mixture suspended homogeneously in the molten
suppository mass. The suspensions are poured into precooled
moulds to give suppositories each weighing 1.7 g.
Exam~e D: Ampoules
(-)-2-(L-tetrahydrofurfuryl)-[(lR,5R,9R)-
2'-hydroxy-5,9-dimethyl-6,7-benzomorphane] 1.0 mg
sodium chloride 10.0 mg
bidistilled water q.s.ad loO ml
- 78 -
~ ~9 5~ :
Production-
The active ingredient and sodium chloride are dissolved in
bidistilled water and the solution filled sterile into
ampoules.
Example E: Dro~s
(t)-2-tetrahydrofurfuryl-2'-hydroxy-5 79~-
dimethyl-6,7-benzomorphane 0.70 g
(racemic diastereomer I~
methyl-p-hydroxy-benzoate 0.07 g
propyl-p-hydroxy-benzoate 0.03 g
demineralized water q.s. ad 100.00 ml
Production:
. . .
The active ingredient and the preservatives are dissolved .
in demineralized water and the solution filtered and filled
înto vials each having a capacity of 100 ml.
- 79 -
.
