Note: Descriptions are shown in the official language in which they were submitted.
~055S~7 AHP-5967-F
BACKGROUND OF THE INV~NTION
The invention relates to benzobicycloalkene amines
which are useful as analgesic agents as well as intermediates
in the preparation of other analgesic agents, benzobicyclo-
alkane amines, and processes for the preparation thereof.
In particular the invention relates to 6,9,10,11-tetrahydro-
5,10-methano-5H-benzocyclononen-12-amines, processes for
their preparation, and their use in alternative processes
for the preparation of 6,7,8,9,10,11-hexahydro-5,10-methano-
5H-benzocyclononen-12-amines.
-- 2
lQ5S5~7 AHP-5~67-F
DESCRIPTION OF THE INVENTION
The invention provides a novel chemical compound
of Formula 1:
Rl ` ~
( 1 )
wherein R is hydrogen, lower alkyl or phen(lower)alkyl;
Rl is methyl, ethyl~ or lower alkenyl; and R2 and R3 are
independently selected from the group consisting of
hydrogen7 lower alkyl, lower alkenyl, lower alkynyl, and
phen(lower)alkyl; and the acid addition salts thereof,
preferably the pharmaceutically effective acid addition
salts. The new compounds of formula 1 in general, in the
acid salt form, are crystalline solids which are sub-
stantially insoluble in ether and are soluble in polar
hydroxylic solvents such as methanol and ethanol.
Examination of compounds produced according to the herein- -
after described process reveals upon infrared and nuclear
magnetic resonance spectrographic analysis, spectral data
supporting the molecular structures herein set forth.
The compounds of formula 1 and their acid addition
salts are useful as intermediates in the synthesis of benzo-
bicycloalkane amines, which are analgesic agents, and inaddition, primary and secondary amine forms o~ compounds of
formula 1 and their pharmaceutically effective acid
addition salts exert analgesic effects in experimental
animals.
1~555~7 AHP-59~7-1~
The invention also provides a process for the
preparation of a compound of formula 1 or an acid addition
salt thereof, which comprises selective reduction of the
group =N-Y of a compound of the formula 2
R0
wherein R and R are as defined above and Y is hydrogen,
hydroxy, lower alkoxy, phen(lower)alkoxy, lower alkyl
or phen(lower)alkyl to form a primary or secondary amine
where R3 is hydrogen and R2 is hydrogen, lower alkyl or
phen(lower)alkyl and, if desired, one or more of the
following steps, namely,
(a) etherifying a compound where R is H to form a compound
where R is lower alkyl or phen(lower)alkyl,
(b) converting a primary amine into a secondary or tertiary
amine conforming with formula 1 or converting a secondary
amine obtained into a tertiary amine conforming with formula 1,
(c) cleaving the ether group of a compound where R is lower
alkyl or phen(lower)alkyl to form a phenolic compound,
(d) resolving a mixture of optical isomers into a diastereo-
meric pair or into an individual enantiomer, and
(e) converting a compound of formula 1 into an acid
addition salt thereof or converting an acid addition salt
form of compound of formula 1 into the free amine.
AHP-59~7-F
1~5SSZ7
The starting materials of formula 2 are novel
compounds and may be prepared by a process described
hereinafter. The selective reduction may be carried out
with an alkali metal, for example, sodium in an alkanol,
for example, ethanol or isopropanol.
When a compound of formula 1 has been obtained
by the selective reduction, it may be subjected to one or
more standard methods to form other compounds of formula 1.
For example, a phenolic compound in which R is hydrogen may
be etherified to form a compound in which R is lower alkyl
or phen(lower)alkyl. The etherification may be carried out
in known manner. For example, a methyl or ethyl ether may
be prepared by reacting the phenolic compound with dimethyl
sulphate or diethyl sulphate in alkaline aqueous medium.
However, it is generally preferable to avoid this step by
selecting an appropriate ether possessing the desired alkyl
or phen(lower)alkyl group as the starting material of
formula 2 for the selective reduction.
~len a primary amine of formula 1 in which R2 and
R3 are hydrogen, or an acid addition salt thereof, has been
formed, it may be converted into a secondary or tertiary
amine using standard methods. Said methods include
reductive alkylation under conditions such that the non-
aromatic double bond of the primary amine is not reduced.
An example of a reductive alkylation of the primary amine
is the formation of the dimethyl tertiary amino derivative
by means of formaldehyde and formic acid. Alternatively
the primary amine may be converted into a secondary amine
in which R is hydrogen and R3 is lower alkyl, lower alkenyl
or lower alkynyl or phen(lower)alkyl, by reaction with a
AHP-5967-F
l~S5S27
halo compound of general formula
31
Hal-R
where Hal is a halogen such as chlorine or bromine or iodine
and R~ is lower alkyl, lower alkenyl, lower alkynyl or
phen(lower)alkyl, preferably in the presence of an organic
base. Similarly a secondary amine in which R is hydrogen
and R3 is lower alkyl, lower alkenyl, lower alkynyl or
phen(lower)alkyl may be converted into a tertiary amine in
which R2 and R3 are both independently selected from lower
alkyl, lower alkenyl, lower alkynyl or phen(lower)alkyl by
reaction with an appropriate lower alkyl halide, lower alkenyl
halide, lower alkynyl halide or phen(lower)alkyl halide.
If desired, a compound of formula 1 or an acid
addition salt thereof where R represents a lower alkyl or
phen(lower)alkyl group may be subjected to cleavage of the
ether linkage to form a phenolic compound where R is hydrogen.
Examples of cleavage agents for splitting ethers include
Lewis acids, for example, aluminium chloride or boron tri-
bromide, and hydrohalic acids, for example, hydrobromic acid.
~0 The compounds of formula 1 possess the property of
optical isomerism and mixtures of the optical isomers may be
resolved into individual isomers. Thus the compounds of
formula 2 may be obtained as racemic mixtures and the
reduction thereof will produce the amines of formula 1 as
diastereomers The separation of the diastereomeric pairs
and their resolution into enantiomers, if desired, may be
accomplished by well-known procedures.
~0555~7 AIIP-5967-F`
The novel compounds of formula 1 may be isolated
as such or in the form of an acid addition salt. The acid
addition salt forms may be prepared by adding an acid to
the compound of formula 1. As the acid from which the
salt may be derived, there may be used hydrochloric, maleic,
citric, acetic, benzoic, or other pharmacologically accept-
able acid. The addition of the acid is preferably carried
out by adding the acid in an alcoholic solution. Acid
addition salts may be converted into the amine itself in
standard manner by adding a base.
The invention also provides a process for the
preparation of a 6,7,8,9,10,11-hexahydro-5,10-methano-5H-
benzocyclononen-12-amine or a pharmaceutically acceptable
acid addition salt by reducing a corresponding 6,9,10,11-
tetrahydro-5,10-methano-5H-benzocyclononen-12-amine or acid
addition salt. Thus, the invention provides a process for
the preparation of a compound of the formula
R ~ ~ ~ ~ ~ (3)
or a pharmaceutically acceptable acid addition salt thereof,
wherein R is hydrogen, lower alkyl or phen(lower)alkyl, Rl
is lower alkyl, R2 is hydrogen, lower alkyl or phen(lower)-
alkyl and R3 is hydrogen, lower alkyl, lower alkenyl, lower
alkynyl, and phen(lower)alkyl, which comprises reduction
of the non-aromatic unsaturated bond or bonds of a compound
of formula 1 as illustrated and defined hereinbefore or an
acid addition salt thereof, and, if desired, one or more of
the following steps:
~HP-~967-F
1~5SS~7
(a) etherifying a compound where R is hydrogen to form a
compound where R is lower alkyl or phen(lower)alkyl,
(b) converting a primary amine into a secondary amine or a
tertiary amine or converting a secondary amine into a
tertiary amine,
(c) cleaving the ether group of a compound where R is lower
alkyl or phen(lower)alkyl to form a phenolic compound,
(d) resolving a mixture of optical isomers into a diastereo-
meric pair or into an individual enantiomer, and
(e) converting a compound of formula 3 into a pharma-
ceutically acceptable acid addition salt or converting an
acid addition salt form of compound of formula 3 into the
free amine.
The products of formula 3 and their pharmaceutically
acceptable acid addition salts are useful as analgesic agents.
Such compounds are described in our Belgian Patent 776,173,
published June 2, 1972.
When a compound of formula 3 has been obtained by
the reduction, it may be subjected to one or more standard
methods to form other compounds of formula 3. For example,
a phenolic compound in which R is hydrogen may be etherified
to form a compound in which R is lower alkyl or phen(lower)-
alkyl. The etherification may be carried out in known
manner. For example, a methyl or ethyl ether may be pre-
pared by reacting the phenolic compound with dimethyl
sulphate or diethyl sulphate in alkaline aqueous medium.
However, it is generally preferable to avoid this step by
AHP-5967-~
1~55S'~7
selecting an appropriate ether possessing the desired alkyl
or phen(lower)alkyl group as the starting material of
formula 1 for the reduction.
When a primary amine of formula 3 in which R and
R3 are hydrogen, or an acid addition salt thereof, has been
formed, it may be converted into a secondary or tertiary
amine using standard methods. Said methods include reductive
alkylation. An example of a reductive alkylation of the
primary amine is the formation of the dimethyl tertiary amino
derivative by means of formaldehyde and formic acid.
Alternatively the primary amine may be converted into a
secondary amine in which R2 is hydrogen and R3 is lower alkyl,
lower alkenyl or lower alkynyl or phen(lower)alkyl, by
reaction with a halo compound of general formula
Hal-R3
where Hal is a halogen such as chlorine or bromine or iodine
31
and R is lower alkyl, lower alkenyl, lower alkynyl or
phen(lower)alkyl, preferably in the presence of an organic
base. Similarly a secondary amine in which R is hydrogen
and R3 is lower alkyl, lower alkenyl, lower alkynyl or phen-
(lower)alkyl may be converted into a tertiary amine in which
R2 is lower alkyl or phen(lower)alkyl and R3 is lower alkyl,
lower alkenyl, lower alkynyl or phen(lower)alkyl by reaction
with an appropriate lower alkyl halide or phen(lower)alkyl
halide. Similarly a tertiary amine in which R3 is lower
alkenyl or lower alkynyl and R2 is lower alkyl or phen(lower)-
alkyl may be prepared from a primary amine where R2 and R3
are hydrogen by reaction with a lower alkyl halide or
phen(lower)alkyl halide to form a secondary amine and
1~555~7 AHP-59~7-F
subsequent reaction with a lower alkenyl halide or lower
alkynyl halide. Alternatively the secondary amine may be
reacted with a haloformate ester and then reduced to give
the tertiary amine in which R is methyl. The haloformate
ester may also be similarly reacted with the primary amine
in which both R2 and R3 are hydrogen to give an N-methyl
secondary amine. Other tertiary amines can be prepared by
acylating the secondary amine to give a compound in which
R is acyl and then reducing the acylated amine.
If desired, a compound of formula 3 or an acid
addition salt thereof where R represents a lower alkyl group
may be subjected to cleavage of the ether linkage to form a
phenolid compound where R is hydrogen. Examples of cleavage
agents for splitting ethers include Lewis acids, for example,
aluminium chloride or boron tribromide, and hydrohalic acids,
for example, hydrobromic acid.
The compounds of formula 3 possess the property
of optical isomerism and mixtures of the optical isomers
may be resolved into an optically active form. Alternatively
optically active forms of compound of formula 3 or its acid
addition salt may be prepared by reducing an optically active
form of compound of formula 1.
The compounds of formula 3 may be isolated as
such or in the form of an acid addition salt. The acid
addition salt forms may be prepared by adding an acid to
the compound of formula 3. As the acid from which the
salt may be derived, there may be used hydrochloric, maleic,
citric, acetic, benzoic, or other pharmacologically acceptable
acid. The addition of the acid is preferably carried out by
- 10 -
AHP-5967-F
105SS;~7
adding the acid in an alcoholic solution. Acid addition
salts may be converted into the amine itself in standard
manner by adding a strong base. A compound of formula 3
or a pharmaceutically acceptable salt thereof may be prepared
from a toxic acid addition salt of the compound of formula 1
provided that the tcxic component is eliminated in the
processing.
In the above identified process for the preparation
of compounds of formula 3, the reduction of the compound of
formula 1 or its acid addition salt is preferably accomplished
by catalytic hydrogenation, for exa~ple, using a Raney nickel
catalyst. It will be appreciated that during the reduction
of the olefinic double bond shown in formula I, any non-
aromatic double bond in Rl, R2 and R3 and any triple bond in
R2 and R3 will be reduced to a single bond. Thus if a final
compound of formula 3 is desired where R3 is lower alkenyl
or lower alkynyl, it is necessary to introduce the group R3
after the reduction.
The compounds of formula 3 and their pharmaceutically
acceptable acid addition salts may also be prepared by direct
reduction of compounds of formula 2 without isolation of
compounds of the formula 1. Thus the invention also provides
a process for the preparation of a compound of formula 3
as illustrated and defined above or a pharmaceutically
acceptable acid addition salt thereof, which comprises
reducing a compound of formula 2 as illustrated and defined
above, and, if desired, one or more of the steps denoted as
(a) to (e) on page 8 herein. The reduction of the compound
of formula ~ is preferably accomplished by catalytic
hydrogenation, for example, using Raney nickel as catalyst.
AI~P-59~7-~
~C~555~7
It will be appreciated that in the reduction product R3 is
hydrogen and R will be hydrogen, in the case of using
starting materials where Y is hydrogen, hydroxy, lower alkoxy
or phen(lower)aLkoxy, or will be the same as Y, i.e. lower
alkyl or phen(lower)alkyl, in the other cases. Where Rl is
a lower alkenyl group in formula 2, the corresponding lower
alkyl group is obtained in the reduction product.
Any subsequent steps such as ether cleavage etc.
may be carried out as described herein on pages 8 to 11.
The compounds of formula 2
_ ~ (2)
where R is hydrogen, lower alkyl or phen(lower)alkyl, Rl
is methyl, ethyl or lower alkenyl, and Y is hydrogen, hydroxy,
lower alkoxy, phen(lower)alkoxy, lower alkyl or phen(lower)-
alkyl are novel compounds provided by this invention. The
invention also provides a process for the preparation of a
novel compound of formula 2, which comprises treating a
compound of the formula 4
R0~ ~ I (4)
where R and Rl are as defined in connection with formula 2
with a compound of the formula H2NY where Y is as defined
above.
- 12 -
1055S~7 AHP-5967-F
Included within the new compounds of the invention
are those of the f~rmula 4
R0 ~ ~ ~ _ ~ (4)
wherein R is hydrogen, lower alkyl or phen(lower)alkyl and
Rl is methyl, ethyl, or lower alkenyl. The new compounds
of formula 4 are, in general, high boiling liquids or
crystalline solids, which are substantially insoluble in
water~ and are soluble in ben~ene, lower alkanols such as
methanol, ketonic solvents such as acetone and methylethyl-
ketone, and the like. Examination of compounds produced
according to the hereinafter described process reveals, upon
infrared and nuclear magnetic resonance spectrographic analysis,
spectral data supporting the molecular structure herein set
forth for the tricyclic ketones.
The invention also provides a process for the
preparation of the tricyclic ketone of the formula 4, which
comprises treating a compound of the formula 5
H~ H
Rl ,C= C
R ~ 0 (5)
where R is lower aLkyl or phen(lower)alkyl, Rl is methyl,
ethyl, or lower alkenyl and X is chlorine or bromine with a
strong base, preferably an alkali metal alkoxide, hydride or
amide, to produce a tricyclic ketone of formula 4 wherein R
is lower alkyl or phen(lower)alkyl and if a ketone in which R
- 13 -
1~555~7 AHP-5967-F
is hydrogen is desired, cleaving the ether linkage to form
the phenolic compound. The strong base employed for the
reaction with the compound of formula 5 is suitably used in
excess amount in an appropriate solvent. The strong base may
be, for example, potassium t-butoxide in t-butanol or sodium
hydride or sodium amide in dimethyl formamide. Where an
ether linkage is to be cleaved~ the cleavage may be carried
out in known manner using, for example, a lewis acid.
The compounds of formula 5 are novel products
provided by the invention. The invention also provides a
process for the preparation of a compound of the formula 5
which comprises treating a compound of the formula 6
RO ~X~ ( 6 )
wherein R iS lower alkyl or phen(lower)alkyl and Rl is
methyl, ethyl or lower alkenyl, with a cis-compound of the
formula
H H
\ C = C (7)
XCH2 CH2X
where X is chlorine or bromine in the presence of a strong
base, preferably an alkali metal lakoxide, hydride or amide.
The strong base is preferably used in excess amount in a
suitable solvent. The product (5) obtained may be used
directly for forming the tricyclic ketone ( 4 ) without
isolation of the adduct (5).
- 14 -
AHP-5967-F
105S5Z7
The starting materials for the preparation of the
adduct (5) are known products or obtainable by known methods.
In particular, cis-1,4-dichloro-2-butene and cis-1,4-dibromo-
2-butene are known compounds. The compounds of formula 6,
namely l-alkyl, or l-alkenyl-tetraLones, ma~ be prepared by
methods described hereinafter.
It will be appreciated that by combining processes
described above, one may synthesize the novel compounds of
formula 1 and also the compounds of formula 3. By way of
example, the following syntheses in accordance with the
invention may be mentioned.
In the first synthesis, a compound of the formula
~ i 3 (8)
wllerein R is lower alkyl or phen(lower)alkyl and Rl is methyl,
methyl or lower alkenyl is prepared by a process which comprises
a. treating a ketone of the formula
Rl
RO ~ (6)
wherein R and Rl are as defined hereinabove in respect of
formula 6 with cis-1,4-dichloro- or 1,4-dibromo-2-butene
in the presence of excess alkali metal alkoxide, hydride, or
arnide to form an adduct compound of the formula
- 15 -
1~55SZ7 AHP-~967-F
Rl CH~CH=CHCH2X
~
wherein R and Rl are as defined hereinabove in respect of
formula 6 and X is chloro or bromo;
b. treating said adduct compound with a second excess
of alkali metal alkoxide, hydride, or arnide to produce a
tricyclic ketone of the formula
R ~ ~ ~ (4)
wherein R and Rl are as defined hereinabove in respect of
formula 6;
c. treating said tricyclic ketone with a compound of
the formula H2NYl wherein yl is hydrogen, hydroxy, lower
alkoxy or phen(lower)alkoxy to produce an imino compound
of the forrnula
Ru~ ~X ~ (10)
wherein R and Rl are as defined hereinabove in respect of
formula 6 and yl is as defined hereinabove; and
- 16 -
lOS5S27 .AHP-5967-F
d. selectively reducing the imino group of said imino
compound.
A second synthesis conforming to the invention is
a process for preparing compounds of the formula
HO ~
wherein Rl is methyl, ethyl, or lower alkenyl which comprises:
a. treating a ketone of the formula
RO~X~ ( 6 )
wherein R and Rl are as defined hereinabove in connection
with formula VI with cis-1,4-dichloro-, or 1,4-dibromo-2-
butene in the presence of excess alkali metal alkoxide,
hydride, or amide to form an adduct compound of the formula
Rl ~H2CH=C~CH2X
RO~ ~ ~ ~0
bJ ~, (9)
wherein R and Rl are as defined hereinabove in connection
with formula 6 and X is chloro or bromo;
lOSS5~7 AHP-5967-F
b. treating said adduct compound with a second excess
of alkali metal alkoxide, hydride, or amide to produce a
tricyclic ketone of the formula:
~ )
wherein R and Rl are as defined hereinabove in connection
with formula 6;
c. treating said tricyclic ketone with a compound of the
formula H2NYl wherein yl is hydrogen, hydroxy, lower alkoxy
or phen(lower)alkoxy to produce an imino compound of the
formula
Ro ` C ~ --J ( lo )
wherein R and Rl are as defined above in connection with
formula 6 and yl is as defined hereinabove;
d. selectively reducing the imino group of said
imino compound to produce a compound of the formula
~ (8)
wherein R and Rl are as defined hereinabove in connection
with forrnula 6, and
- 18 -
10555~7 AHP-5967-F
e. cleaving the ether function.
A third synthesis according to the invention is a
process for preparing compounds of the formula
RO~ ] (12)
wherein R iS lower alkyl, or phen(lower)alkyl; and Rl is
methyl, or ethyl, which comprises:
a. treating a ketone of the formula
RO~ (6)
wherein R and Rl are as defined hereinabove in connection
with formula 12 with _ s-1,4-dichloro-, or 1,4-dibromo-
2-butene in the presence of excess alkali metaL alkoxide,
hydride~ or amide to form an adduct compound of the formula
Rl CH,CE~-=CHCH2X
R~ (9)
wherein R and Rl are as defined hereinabove in connection
with formula 12 and X is chloro or bromo;
b. treating said adduct compound with a second excess
of alkali metal alkoxide, hydride, or amide to produce a
tricyclic ketone of the formula
-- 19 --
AHY-5967-F'
~ ~ (4)
wherein R and Rl are as defined hereinabove in connection
with formula 12 ;
c. treating said tricyclic ketone with a compound of
the formula H2NYl wherein yl is hydrogen, hydroxy, lower
alkoxy or phen(lower)alkoxy to produce an imino compound
of the formula
R l~ ) (10)
wherein R and Rl are as defined above in connection with
formula 12 and yl is as defined hereinabove; and
d. selectively reducing the imino group to produce a
compound of the formula
~ ~ 1 (8)
wherein R and Rl are as defined hereinabove in connect ion
with formula 12; and
e. reducing the non-aromatic double bond.
- 20 -
l~SSSZ7 AHP-59~7-F`
The invention also provides a process for the
preparation of a chemical compound of the formula
~ (13)
wherein R iS lower alkyl, or phen(lower)alkyl; and Rl is
methyl, or ethyl, which comprises:
a. treating a ketone of the formula
Rl
RO~O (6)
wherein R and Rl are as defined hereinabove in connection
with formula XIII with cis-1,4-dichloro-, or 1,4-dibromo-
2-butene in the presence of excess alkali metal alkoxide,
hydride, or amide to form an adduct compound of the formula
Rl CH2CH=CHCH2X
R~O (g
wherein R and Rl are as defined hereinabove in connection
with formula 13 and X is chloro or bromo;
b. treating said adduct compound with a second excess
of alkali metal alkoxide, hydride, or amide to produce a
tricyclic ketone of the forrnula
- 21 -
~0555~7 AHP-5967-F
~ (4)
wherein R and Rl are as defined hereinabove in connection
with formula 13;
c. treating said tricyclic ketone with a compound of
the formula H2NYl wherein yl is hydrogen, hydroxy, lower
alkoxy or phen(lower)alkoxy to produce an imino compound of
the formula
~or~ , (10)
wherein R and Rl are as defined in connection with formula
1~ above and yl is as defined hereinabove; and
d. reducing the imino and non-aromatic double bonds.
A fifth synthesis of the invention resides in a
process for the preparation of chemical compounds of the
formula
~ ) (14)
wherein Rl is methyl or ethyl; which comprises:
- 22 -
1055SZ7 Al~-5967-F
a. treating a ketone of the formula
RO ~ (6)
wherein Rl is methyl or ethyl and R is lower alkyl or
phen(lower)alkyl with cis-1,4-dichloro-, or 1,4-dibromo-
2-butene in the presence of excess alkali metal alkoxide,
hydride, or amide to form an adduct compound of the formula
Rl CH~,CH=CHCH2X
RO ~ o
11 ~ (9)
~W
wherein Rl is methyl or ethyl and R is lo~er alkyl or
phen(lower)alkyl and X is a chloro or bromo;
b. treating said adduct compound with a second excess
of alkali metal alkoYide, hydride, or amide to produce a
tricyclic ketone of the formula
Rl
~ XX3
wherein R is lower alkyl or phen(lower)alkyl and Rl is
methyl or ethyl;
- 23 -
AHP-5967-F
10555;~7
c. treating said tricyclic ketone with a compound of
the formula H2NYl wherein yl is hydrogen, hydroxy, lower
alkoxy or phen(lower)alkoxy to produce an imino compound of
the formula
.~ r3 (lo)
wherein R is lower alkyl or phen(lower)alkyl, Rl is methyl
or ethyl and yl is as defined hereinabove;
d. selectively reducing the imino group,
e. cleaving to produce a compound of the formula
HO ~
wherein Rl is methyl or ethyl; and
f. reducing the non-aromatic double bond.
In describing the process for the preparation of
a specific embodiment of the invention, reference will be
made to the accompanying drawing wherein the compounds are
assigned Roman Numerals for identification schematically, and
wherein is illustrated the synthesis of specific embodiments
of Formula 1 namely 12-amino-5-ethyl-6,9,10,11-tetrahydro-
5,10-methano-[5H~-benzocyclononen 3-ol (X), and 5-ethyl-
6,9,10,11-tetrahydro-3-methoxy-5,10-methano-[51~-benzo-
cyclononen-12-amine (IX), and a specific embodiment
- 24 -
1~55S~7 AHP-5967-F
of Formula 4 namely 5-ethyl-6,7,10,11-tetrahydro-3-methoxy-
5,10-methano-[5H~-benzocyclononen-12-one (III). The drawing
also illustrates the use of the process aspect of the
invention for the preparation of specific 6,7,8,9,.10,11-
hexahydro-5,10-methano-[5HI-benzocyclononen-12-amines,
namely 5-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-
methano-5H]-benzocyclononen-12-amine (VIII) and 12-amino-
5-ethyl-6,7,8,9,10,11 hexahydro-5,10-methano-[5H~-
benzocyclononen-3-ol (XI).
1-Ethyl-7-methoxy-2-tetralone (III) and excess
_ -1,4-dichloro-2-butene (IV) are treated, conveniently at
room temperature, in an inert atmosphere, with a slight
excess of 1 equivalent of a strong base, conveniently
potassium t-butoxide, for a period of from about 12 to about
24 hours, conveniently about 18 hours to produce compound V.
Isolation of compound V is not required and treatment of the
reaction mixture containing it with a further excess of the
strong base followed by a period of warming, conveniently
6 hours at the reflux temperature of the solvent employed,
which is in turn followed by an additional period of reaction
which is conveniently allowed to proceed at room temperature
for about 16 additional hours. The exact times and tempera-
tures of reaction, are not, of course, critical. The strong
base to be employed as well as the appropriate solvent is
similarly not especially critical and many suitable combina-
tions, such as potassium t-butoxide in t-butanol, and
sodium hydride or sodium amide in dimethyl formamide, will
occur to the skilled organic chemist; if potassium t-butoxide
is the strong base employed, t-butanol is a particularly
- 25 -
AHP-59~7-F
1055SZ7
convenient solvent. The compound VI, so produced is then
isolated by standard procedures. The oxime VII is then
prepared by treating compound VI with hydro~ylamine in an
inert solvent, conveniently methanol, initiaLly at elevated
temperature, conveniently the reflux temperature of the
solvent employed, for a short period of time, conveniently
6 hours, followed by a more extended period, conveniently
18 hours, at room temperature. Compound VII is recovered by
standard means. Compound VII may, if desired, be reduced
directly to compound VIII; catalytic hydrogenation is a
particularly convenient means for this transformation.
Cleavage of compound VIII to produce compound XI may, if
desired, be accomplished in the usual fashion by treatment
with such hydrohalic acids as hydrogen bromide or hydrogen
iodide in hot aqueous solution. Alternatively, if desired,
the oximino function of compound VII may be selectively
reduced, the Bouveault Blanc method being especially
convenient, to produce compound IX. If desired, compound IX
mny be reduced to produce compound VIII. Catalytic
hydrogenation is particularly convenient for accomplishing
this reduction. Compound IX may, if desired, be cleaved,
conveniently with a Lewis acid such as boron tribromide, to
produce compound X. If desired, compound X may be reduced
to produce compound XI. Catalytic hydrogenation is con-
venient for accomplishing this reduction. Isolati~n of
compounds VIII, IX, X, and XI may, if desired, be
accomplished by standard means.
While the process of the invention has heen
described with reference to the dra-~ing which illustrates
its application to 1-ethyl-7-methoxy-2-tetralone it will be
- 2G -
lOSSS27 1~P-5967-F
readily apparent that the process will be equally applicable
to other tetralones bearing in the 1 and 7 positions the
various substituents contemplated within the scope of the
invention.
The preparation of the variously substituted
secondary and tertiary amines contemplated to be within the
scope of the invention is similarly obvious, and standard
methods for this purpose are well-known to those skilled in
the art. For example, dimethyl tertiary amino derivatives
may be prepared by means of a Leuchart-Wallach reaction
utilizing formic acid and formaldehyde.
The skilled organic chemist will similarly
recognize that the ether linkage of compound VI may be
cleaved in a fashion similar to that of the cleavage of the
ether linkage of compound IX. The phenolic compound so
produced will, of course, be fully equivalent to compound VI
for purposes of further transformations. It is obvious that
the other tricyclic ketones of Formula 4 contemplated within
the scope of the invention which have an ether in the three
position may be similarly cleaved to the corresponding
phenolic compound, which, of course, will be the full
equivalent of the non-phenolic compounds for the purposes
of further reactions.
The starting materials for the practice of the
invention, namely l-alkyl-, or l-alkenyl-2-tetralones, may
be prepared from readily available 2-tetralones, by a
well-known alkylation reaction as typically described in
Stork and Schulenberg in the Journal of the American Chemical
Society, 84, 284, (1962). The tetralones are treated with
~555~7 AHP-5967-F
pyrrolidine in an inert solvent such as benzene, and then
reacted with an appropriate lower alkyl-, or lower alkenyl-
halide in an inert solvent, such as benzene or dioxane, at
elevated temperatures~ conveniently the reflux temperature
of the solvent employed. They may also be prepared from a
suitable commercially available l-tetralone which may be
treated as described by Howell and Taylor in the Journal of
the Chemical Society, 1958, 1249 with a Grignard reagent,
prepared from an appropriate lower alkyl-, or lower alkenyl-
halide, and the resulting l-substituted dihydronaphthalene
oxidized with peracid.
Many of the tetralones are commercially available,
and syntheses, for those which are not, are readily available
in the literature. For example, the synthesis of ~-tetralone
is described in Organic Synthesis, Collective Volume IV,
page 898; the synthesis of ~-tetralone is described in the
same work on page 903; and a general synthesis of ~-tetralones
is described by Nagata et al. in Netherlands Patent 67,09534,
January 10, l9G8.
It will be obvious to one skilled in:the art of
chemistry that the ketones of Formula 4 will be produced as
racemic mixtures and that reduction of oximes thereof will
produce the amines of Formula 1 as diastereomers. The
separation of the diastereomeric pairs and their resolution
into enantiomers, if desired, may be accomplished by well-
known procedures. The diastereomers, enantiomers, and
mixtures thereof are all included within the scope of this
invention. The analgesic activity of the compounds of
formula 1 and their pharmaceutically suitable acid addition
salts can be elicited by following a modification of the test
- 28 -
1055527 AHP-5967-F
procedure described by D'Amour and Smith in Journal of
Pharmacology, 72, 74 (1941) an accepted test for analgesic
agents. In this test, rats are administered the compound
orally, intraperitoneally, and intramuscularly, and the
time required for response to a pain stimulus caused by a
high intensity beam of light shining on the tail measured.
The compounds of formula 1 and their pharmaceutically
suitable acid addition salts exhibit analgesic activity in
rats at dosages greater than 1.56 mg. per kg. intraperi-
toneally and particularly at doses of from 6.25 to 25.0 mg.
per kg.
6,7,8,9,10,11-Hexahydro-5,10-methano-5H-benzocyclo-
nonen-12-amines which are the useful products of a number of
the alternative processes of the invention also induce
analgesic activity in warm-blooded animals and are described
Belgian Patent 776,173, June ~, 1972.
When the compounds of Formula 1 and their pharma-
ceutically effective acid addition salts are employed as
analgesic agents they may be administered to warm-blooded
animals, e.g. mice, rats, rabbits, monkeys, and so forth,
alone or in combination with pharmacologicaLly acceptable
carriers.
The dosage employed upon administration of the
compounds of the invention will vary with the form of
administration and the compound chosen. Furthermore, it will
vary with the particular subject under treatment. Generally,
treatment is initiated with small dosages substantially less
than the optimum dose of the compound. Thereafter the
dosage is increased by small increments until the optimum
- 29 -
10555~7 AHP-5967-F
effect under the circumstances is reached. In general, the
compounds of the invention are most desirably administered
at a concentration level that will generally afford
effective results without causing any harmful or
deleterious side effects.
As used herein the term "lower alkyl" means a
saturated hydrocarbon radical, including the straight and
branched radicals, having from 1 to 6 carbon atoms, among
which are, for the purposes of illustration, but without
limiting the generality of the foregoing methyl, propyl and
i-butyl. The term "lower alkenyl" means an unsaturated
hydrocarbon radical, including straight and branched radicals,
having from 3 to 5 carbon atoms, among which are for the
purposes of illustration, but without limiting the generality
of the foregoing, allyl, 2-butenyl, 3-methyl-2-butenyl and
2-pentenyl. The term "phen(lower)alkyl" means a lower
alkyl radical as hereinbefore defined substituted in a
terminal position by a phenyl radical, or by a phenyl radical
substituted by lower alkyl or lower alkyloxy radicals, among
which are, for the purposes of illustration, but without
limiting the generality of the foregoing, benzyl, phenethyl,
o-, m-, p-anisyl veratryl, and o-, m-, or p-xylyl.
The following examples further illustrate the
invention.
- 30 -
1~55527 AHP-5967-F
Exam~le I
6,9,l0~11-tetr~lydro-3-Methoxy-5-Methyl-5,10-Methano-
__
5f~-Benzocyclononen-12-One
_ . _
Under an atmosphere of nitrogen, a solution of
l-methyl-7-methoxy--2-tetralone (40 g., 0.21 M) in t-butanol
(100 ml.) is added, dropwise, to a freshly prepared solution
of potassium t-butoxide (9.8 g., 0.25 M potassium in 400 ml.
t-butanol). The mixture is stirred at room temperature for
1 hour after addition is complete, then transferred, under
nitrogen, to a dropping funnel, and added dropwise to a
solution of cis-1,4-dichloro-2-butene (53 g., 0.42 M) in
t-butanol, while stirring under nitrogen. Stirring is allowed
to contimle for about 18 hours, after adding 1 g. of potassium
iodide, at room temperature. An additional quantity of fresh
potassium t-butoxide solution (15 g., 0.38 M of potassium in
400 ml. t-butanol) i.s then added dropwise, and the mixture
refluxed for 6 hours following completion of the addition.
Following the reflux period stirring is continued at room
temperature for about 16 hours. The reaction mixture is then
poured into water (appro~imately 4 liters) and the organic
phase extracted into benzene. The benzene solution is washed
twice with water, dried over magnesium sulphate, and the
solvent stripped in vacuo to yield a crude oil (57 g.~.
Distillation of the crude oil yields a product (36 g.)
B. P. 155-165 (0.5 mm.) which is crystallized from hot
heptane m.p. 79-81.
- 31 -
10555Z7 .~IP-59~7-F`
Example II
6,9,10,11-Tetrahydro-3_Met~ -5-M_thyl-5,10-Methano-
5~-Benzocyclononen-12-One, Oxime
A clear solution of sodium acetate (23 g.) in
methanol (15 ml.) is mixed with a clear solution of hydroxyl-
amine hydrochloride (19.5 g.) in methanol (200 ml.) and the
resulting precipitate of sodium chloride separated by
filtration. To this mixture is added a solution of 6,9,10,11-
tetrahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-
12-one (13.5 g.) in methanol (50 ml.). When addition is
complete, the reaction mixture is refluxed for about 4 hours,
and then let stir for about 16 additional hours. The solvents
are then stripped in vacuo and the residue slurried in water
to give a solid which is separated by filtration, worked
thoroughly with water and dried to give a product 14.2 g.,
m.p. 122-125. Recrystallization from isopropanol give5
the title product 11.7 g., m.p. 124-126.
Example III
6,7,8,9,10,11-Hexahydro-3-Methoxy-5~-Methyl-5,10-Methano-
~
6,9,10,11-Tetrahydro-3-methoxy-5-methyl-5,10-
methano-5H-benzocyclononen-12-one, oxime (5 g.), ethanol
(150 ml.), concentrated ammonium hydroxide (30 ml.), and
Raney nickel (2 tsps.) are shaken with hydrogen at 40 psi.
pressure for 5 hours at room temperature.
The catalyst is separated by filtration, and solvents
removed _ vacuo. The residual oil is partitioned between
lOS5527 ~IP-5967-F
ether and water. Separation of the ether layer, drying over
magnesium sulphate, and removal of the ether in vacuo gives
a crude product, 4.5 g.
Treatment of an ether solution of the crude product
with anhydrous hydrogen chloride gives a precipitate, 3.5 g.,
m.p. 265-272. Recrystallization from hot water gives the
title product as the hydrochloride salt, 1.6 g., m.p.
301-303.
Example IV
5-Ethyl-6,9~10,11-Tetrahydro-3-Methoxy-5,10-Methano-
5H-Benzocyclononen-12-One
Following a procedure analogous to that used in
Example I for the preparation of 6,9,10,11-tetrahydro-3-
methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one,
there is obtained from l-ethyl-7-methoxy-2-tetralone (20.4 g.)
and ci~s-1,4-dichloro-2-butene (25 g.), 17.8 g. of the title
product, b.p. 150-185 (0.4 mm.).
Example V
5-Ethyl-6,9,10,11-Tetrahydro-3-Methoxy-5,10-Methano-
5H-Benzocyclononen-l~-One, Oxime
Following a procedure analogous to that used in
Example II for the preparation of 6,9,10,11-tetrahydro-3-
methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one,
oxime, there is obtained from 5-ethyl-6,9,10,11-tetrahydro-
3-methoxy-5,10-methano-5H-benzocyclononen-12-one (16.0 g.),
and a clarified mixture of sodium acetate (25.5 g.) and
hydroxylamine hydrochloride (2~ g.) in methanol (200 ml.),
10.3 g. of the title product, m.p. 150-153.
- 33 -
lOS55;~7 A}IP-5967-1l
Example VI
5(x-Ethyl-G,7,8, 9L10 ,11 Hexahydro-3-Methoxy-5,10-Methano-
5H-Benzocyclononen-12~-Amine
Following a procedure analogous to that used in
Example I[I for the preparation of 6,7,8,9,10,11-hexahydro-
3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-amine,
there is obtained from 5-ethyl-6,9,10,11-tetrahydro-3-
methoxy-5,10-methano-5H-benzocyclononen-12-one, oxime
(3.0 g.), 1.4 g. of the hydrochloride salt o the title
product, m.p. 2~7-250.
Example VII
6,9 2 10 ~ ll-Tetrahydro-3-Methox _ ~-Methyl-5~10-Methano-
5H-Benzocyclononen-12~-Amine
Add, over an approximately 90 minute period, clean
sodium pellets (4.4 g.) to a stirring, refluxing solution of
6,9,lO,ll-tetrahydro-3-methoxy-5-methyl-5,10-methano-5H-
benzocvclononen-12-one, oxime (2.5 g.) in dry ethanol
(2.5 ml.), while maintaining a blanket of nitrogen. After
completion of the addition, refluxing and stirring is
continued for approximately 1 hour. The reaction is cooled
to 20 and diluted with dry ethanol (25 ml.). Stirring is
contimled until sodium fragments are no longer visible. The
solution is again cooled to 20 and an ice-water mixture
(approximately 200 ml.) is added to it. The ethanol is
removed by concentration in vacuo, and the remaining aqueous
solution partitioned with ether. The ether fraction is
washed with saline, dried over sodium sulphate and
- 3~ -
1055527 AHP-5967-F
concentrated in vacuo to an oil. This oil is taken up in
-
ether and treated with excess dry hydrogen chloride to form a
product, 2.07 g., m.p. 287-289 (dec.). Recrystallization of
this product from methanol-water acidified with concentrated
hydrochloric acid gives the hydrochloride salt of the title
product, 1.56 g , m.p. 300-302.
Analysis for: 16H22ClN
Calculated: C, 68.68; H, 7.93; N, 5.01; Cl, 12.67
Found: C, 68.81; H, 8.23; N, 5.21, Cl, 12.38
NMR Analysis: Signal at ~=5.55, 5.1 (triplets, total
2 protons) ppm.
Example VIII
5a-Ethyl-6,9,10,11-Tetrahydro-3-Methoxy-5,10-Methano-
5H-~en-oc~clononen-12~-Amine
Following a procedure analogous to that used in
Example VII for the preparation of 6,9,10,11-tetrahydro-3-
methoxy-5~-methyl-5,10-methano-5H-ben~ocyclononen-12~-amine,
there is obtained from 5-ethyl-6,9,10,11-tetrahydro-3-methoxy-
5,10-methano-5H-benzocyclononen-12-one, oxime (3.8 g.),
1.76 g. of the title product, m.p. 77-78 as well as a second
crop, 0.6 g., m.p. 74-76.
Analysis for: C17H23N
Calculated: C, 79.33; H, 9.01; N, 5.44
Found: C, 79.36; H, 9.35; N, 5.38
MMR Analysis: Signals at ~=5.2 (broad, multiplet) ppm.
Mass spectral analysis:
Calculated: m/e 257.0
Found: m/e 257.0
~ o S s s ~ AHP-5967-F
The second crop material of the free base together
with sufficient first crop material to total approximately
0.7 g. is dissolved in ether and treated with excess dry
hydrogen chloride gas to produce the hydrochloride salt of the
title product, 0.98 g., m.p. 285-286.
Analysis for: C17H24C1N
Calculated: C, 69.49; H,8.23; N, 4.77; Cl, 12.07
Found: C, 69.14; H, 8.66; N, 4.78; Cl, 12.32
Example IX
10 12~-Amino-5a-Ethyl-6,9,10,11-Tetrahydro-5,10-Methano-
5H-Benzocyclononen-3-01
A solution of 5-ethyl-6,9,10,11-tetrahydro-3-
methoxy-5,10-methano-5~-benzocyclononen-12-amine (3.0 g.) in
dry methylene chloride (100 ml.) is cooled to -20 while
being blanketed under nitrogen, a solution of boron tribromide
(6.7 g.) in dry methylene chloride is added over a period of
30 mimltes whi~e continuing to maintain the temperature at
about -2G and stirring. When addition is complete the
reaction is allowed to warm to room temperature, and stirring
under nitrogen is continued for about 16 hours. After cooling
the reaction mixture to 0, cold water (150 ml.) is added and
stirring contimled for about 1 hour. The layers formed on
standing are separated, and the water layer made basic with
concentrated ammonium hydroxide. Filtration is used to
separate a product which separates, 2.1 g., m.p. 178-186.
Recrystallization from methanol gives the title product,
0.7 g., m.p. 216-218.
- 36 -
lOSSS~ AHP-5967-F
Example X
N,NL5~-Trimethyl-6,9,10,11-Tetrahydro-3-Methoxy-5,10-Methano-
5H-Benzocyclo onen-12~-Amine
6,9,10,11-Tetrahydro-3-methoxy-5~-methyl-5,10-
methano-5H-benzocyclononen-12~-amine (5 g.) is dissolved in
90% formic acid ~5.2 g.). 40% Aqueous formaldehyde (4.5 ml.)
is added, and the stirred solution is warmed slowly. When the
temperature of the solution reaches 40, a vigorous evolution
of C2 commences. When the reaction temperature begins to drop,
external heating is resumed, and the reaction is maintained
at 90 for 8 hours. After cooling, the reaction mixture is
concentrated _ vacuo. The residue is dissolved in water,
excess dilute sodium hydroxide solution is added and the
mixture partitioned with ether. The ether portion is washed
with saline, dried over sodium sulphate and concentrated
in vacuo to an oil, 4.8 g. This oil is dissolved in ethanol
and treated with excess hydrogen chloride gas. On standing the
hydrochloride salt of the title product separates, as crystals,
3,5 g., m.p. 2?8-230.
O Analysis for: C18H26ClN
Calculated: C, 70.22; H, 8.51; N, 4.55; Cl, 11.52
Found: C, 70.31; H, 8.68; N, 4.34; Cl, 11.84
Example XI
N,NL-Dimethyl-6,9,lO,ll Tetrahydro-3-Methoxy-5~-Ethyl-
5 10-Methano-5H-Benzocyclononen-12~-Amine
_ __
Following a procedure analogous to that described
in Example X for the synthesis of N,N,5~-trimethyl-6,9,10,11-
tetrahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12~-amine,
- 37 -
lOS~ AHP--5967-F
there is obtained from 6,9,10,11-tetrahydro-3-methoxy-5~-ethyl-
5,10-methano-5H-benzocyclononen-12~-amine, the title product
which is converted by standard means to its hydrogen chloride
salt, m.p. 236-237.
Analysis for: Cl9H28NCl
Calculated: C, 70.89; H, 8.77; N, 4.35; Cl, 11.02
Found: C, 70.90; H, 8.97; N, 4.31; Cl, 10.70
Example XII
5~-Ethyl-6,9~10,11-Tetrahydro-3-Methoxy-N-Methyl-5,10-Methano-
5H-Benzocyclononen-12~-Amine
A solution of 5~-ethyl-6,9,10,11-tetrahydro-3-
methoxy-5,10-methano-5H-benzocyclononen-12~-amine (6.5 g.~
0.25 M) and methyl iodide (4.0 g.) in acetone (200 ml.) is
refluxed for a period of 12 hollrs. The solution is cooled to
room temperature, and the hydroiodide salt of the title product,
which separates as a white precipitate, is removed by
filtration (5.3 g.~, m.p. 251-254C.
Partitioning the hydroiodide salt between ether and
dilute sodium hydroxide solution, followed by drying of the
ethereal solution over Mg S04 and treatment with excess
hydrogen chloride gives the hydrochloride salt of the title
product as a white precipitate which is recovered by filtra-
tion and recrystalli~ed from ethanol, 2.6 g., m.p. 279-281.
Analysis for: C18H~6ClN0 l/4 H20
Calculated : C, 69.21; H, 8.39; N, 4.48
Found: C, 69.53; H, 8.64; N, 4.42
- 38 -
10555~7 AHP-5967-F
Example XIII
Resolution of 5~-Ethyl-6,9,10,ll-Tet ~ -Methoxy-
.
5,10-Methano-5H-Benzocy~ onen-12~-Amine
__
A. To a solution of 50 g. of d-tartaric acid in
1 5 liters of methanol is added a solution of 76.5 g. of
5~-ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methano-5H-
benzocyclononen-12~-amine in methanol. The resultant
solution is diluted to 3.0 liters and allowed to stand
overnightO Filtration gives 56 g. of salt with m.p. 199-202
dec. Three recrystallizations of this salt from methanol
give 28.4 g. of salt with m.p. 209-211 dec. and
[~ID5 -47 6
The salt is converted to free base by
partitioning with dilute sodium hydroxide and ether. The
ether portion, after drying, is concentrated to give 17 g.
of base which crystallizes on standing, m.p. 50-53,
L~ID5 -85 4
A 4 gram portion of base is converted to its
hydrochloride salt in ether. Revrystallization of the salt
from ether-ethanol gives 4.0 g. with m.p. 27~-275,
[~D5 -69 6
Analysis for: C17H24NCl
Calculated: C, 69.49; H, 8.23; N, 4.77
Found: C, 69.33; H, 8.51; N, 4.63
B. The mother liquors from the recrystallization
of the d-tartarate salt of Part A above are combined and
concentrated. The residue is converted to free base by
partitioning between ether and dilute sodium hydroxide.
- 39 -
10 55 SZ 7 AHP-5967-F
The ether portion is dried and concentrated to give 50 g.
of crude base. This base is dissolved in methanol and
added to a solution of 33 g. of (l)-tartaric acid in
methanol. The resultant solution is diluted to 2.8 liters
and allowed to stand overnight. Filtration gives 55 g. of
salt with m.p. 200-205. Two recrystallizations of this
salt from methanol give 31.4 g. of salt with m.p. 210-211
dec. and La]D5 +47.7.
The salt is converted to base in the same
manner as the (-) rotamer of above to give 19 g. which
crystallized on standing, m.p. 48-51, [a]25 +84.3.
A 4 g. sample is converted to hydrogen
chloride salt which on recrystallization from ethanol-ether
has m.p. 260-265, [a]D5 +69.3.
Analysis for: C17H24NCl
Calculated: C, 69.49; H, 8.23; N, 4.77
Found: C, 69.60; H, 8.59; N, 4.69
E~ample XIV-
(+)-12~-Amino-5a-Ethyl-6,9,10,11-Tetrahydro-5,10-Methano-
5H-Benzocyclononen-3-01
Following a procedure analogous to that described
in Example IX for the preparation of 12~-amino-5a-ethyl-
6,9,10,11-tetrahydro-5,10-methano-5H-benzocyclononen-3-ol,
there is obtained from 15 g. of (+) 5~-ethyl-6,9,10,11-
tetrahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12~-
amine, 11.4 g. of solid ba~e with m.p. 167-172. This is
- 40 -
105S527 AHP-5967-F
converted to its hydrogen chloride salt in methanol-ether.
recrystallization of the salt from ethanol-ether gives
12.0 g. of (+) salt with m.p. 261-263 [~ID5 +83Ø
Analysis for: C16H22NC~-
Calculated: C, 68.68; H, 7.93; N, 5.01
Found: C, 68.53; H, 8.25; N, 4.89
AIIY-59fi7f
lOS5S;~7
Example XV
(-) 12~-Amino-5~-Ethyl-6,9,10,11-Tetrahydro-5,10-
Methano-5H-Benæocyclononen-~-01
Following a procedure analogous to that described
in Example IX for the preparation of 12~-amino-5a-ethyl-6,9,
10,11-tetrahydro-5,10-methano-5H-benzocyclononen-~-ol there
is obtained from 1~ g. of (-) 5a-ethyl-6,9,10,11-tetrahydro-
~-methoxy-5,10-methano-5H-benzocyclononen-12~-amine, 9.0 g.
of solid base. This is converted to its hydrogen chloride
salt in methanol-ether. Recrystallization of the salt from
ethanol-ether gives 7.5 g. of (-) salt with m.p. 260-262,
t~]2D5 -82 8
Analysis for C16H22NCl
Calculated: C, 68.68; H, 7.9~; N, 5.06
Found: C, 68.80; H, 8.2~; N, ~.91
Example XVI
12~-Amino-5~-Methyl-6,9,10,11-Tetrahydro-5,10-
Methano-511-Benzocyclononen-~-01
Following a procedure analogous to that described in
Example IX for the preparation of 12~-amino-5a-ethyl-6,9,10,11-
tetrahydro-5,10-methano-5H-benzocyclononen-~-ol, there is
obtained from 6,9,10,11-tetrahydro-~-methoxy-5~-methyl-5,10-
methano-5H-benzocyclononen-12~-amine 2.0 g., 0.25 g. of the
hydrochloride addition salt of the title product as an ethanol
solvate, m.p. 180 C. (decomp.).
lOSSSZ7
SUPPLEMENTARY DISCLOSURE
It has now been found that the class of novel
chemical compounds described in the principle disclosure may
be enlarged by expanding the definition of Rl in formulae 1, 2,
4, 5, 6, and 7 to include methyl, ethyl, lower alkyl or lower
alkenyl. The followinq examples illustrate the preparation of
these compounds wherein Rl is lower alkyl.
EXAMPLE XVII
6,9,10,11-Tetrahydro-3-Methoxy-5-Propyl-
5,10-Methano-5H-Benzocyclononen-12-One
A solution of l-propyl-7-methoxy-2-tetralone (0.1 mole)
in t-butanol (60 ml.) is added to a solution of potassium t-buto-
xide (0.12 mole) in t-butanol (200 ml.). After stirring one hour
this mixture is added dropwise to a solution of cis-1,4-dichloro-
2-butene (0.2 mole) in t-butanol (200 ml.). 2G of potassium
iodide is added and the mixture stirred overnight. A solution
of potassium t-butoxide (0.18 mole) in t-butanol (200 ml.) is
then added, and the mixture stirred at reflux for 6 hours. The
reaction mixture is cooled and poured into 4 liters of water and
the resulting mixture extracted with benzene. After separation
the combined benzene extracts are dried over magnesium sulfate,
the solvent removed, and the residue is distilled to give the
title compound in adequate purity for further synthesis.
EXAMPLE XVIII
6,9,10,11-Tetrahydro-3-Methoxy-5-Propyl-5,10-Methano-
5H-Benzocyclononene-12-One, Oxime
To a solution of hydroxyl amine (0.3 mole) i}~ methanol
(500 ml.) add 6,9,10,11-tetrahydro-3-methoxy-5-propyl-5,10-
methano-5H-benzocyclononen-12-one (0.06 mole) in methanol (50 ml.).
r'he solution is then refluxed for six hours. The solvent was
removed and the residue recrystallized from ethanol to give the
title product in sufficient purity for further synthetic work.
43 -
10555Z7
~Y~ PLE XIX
6,9,10,11-Tetrahydro-3-Methoxy-5-Propyl-
5,10-Methano-5H Benzocyclononen-12-Amine
To a stirred solution of 6,9,10,11-tetrahydro-3-
methoxy-5-propyl-5,10-methano-5_-benzocyclononen-12-one, oxime
(0.010 mole) in ethanol (2.5 ml.) add (slowly over a period of
90 minutes) sodium pellets (4.4.g.). The resulting mixture is
then heated at reflux for 1 hour, cooled, and ethanol (25 ml.)
added. When all visible particles of sodium metal are absent,
the mixture is again cooled and added to ice water (200 ml.).
The ethanol is removed by evaporation and the resulting aqueous
mixture is partitioned with ether. The combined ether extracts
are dried over magnesium sulfate, and the ether solvent is
removed to give the title product. The hydrogen chloride salt
is prepared in the usual fashion by adding dry hydrogen
chloride to an ether solution of the free base.
EXAMPLE XX
6,7,8,9~10,11-Hexahydro-3-Methoxy-5-Propyl-
5,10-Methano-5_-Benzocyclononen-12-Amine
A mixture of 6,9,10,11-tetrahydro-3-methoxy-5-propyl-
5,10-methano-5_-benzocyclononen-12-one, oxime, Raney nickel
(2 teaspoons), ethanol (150 ml.) and concentrated aqueous
ammonia (30 ml.) is shaken with hydrogen at 45 psi for 5 hours.
The catalyst is separated by filtration and the filtrate
concentrated to give the title product. Treatment of the base
with fumaric acid in acetone gives the fumarate salt with m.p.
226-227.
