CA1055527A - Processes for the preparation of benzobicycloalkene amines and related compounds - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Benzobicycloalkene amines of the formula:

Description

~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.

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 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 l~S5S27 halo compound of general formula 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 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 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.

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

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) 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).

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 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 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 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 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.

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 ~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:

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;

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 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 AHP-59~7-F

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 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 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 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.

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.

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.

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~ -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.

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, 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 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.

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 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.

~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.

Claims (46)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of the formula:

wherein R is lower alkyl: and R1 is methyl or ethyl, which comprises:
a. treating a ketone of the formula:

wherein R and R1 are as defined hereinabove with cis-1,4-di-chloro-, 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:

wherein R and R1 are as defined hereinabove 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 tri-cyclic ketone of the formula:

wherein R and R1 are as defined hereinabove;
c. treating said tricyclic ketone with a compound of the formula H2NY wherein Y is hydrogen, hydroxy, lower alkoxy or phen(lower)alkoxy to produce an imino compound of the formula:

wherein R, R1, and Y are as defined hereinabove; and d. selectively reducing the imino group of said imino compound.

2. A process as defined in claim 1 wherein a Bouveault Blanc type reduction is used to selectively reduce the imino group.

3. A process for the production of a compound of the formula:

wherein R1 is methyl or ethyl which comprises:

a. preparing, by the method of claim 1, a compound of the formula:

wherein R is lower alkyl and R1 is as defined hereinabove;
and b. cleaving the ether function.

4. A process as defined in claim 3 wherein a Lewis Acid is the cleavage reagent.

5. A process as defined in claim 4 wherein the Lewis Acid is boron tribromide.

6. A compound of the formula:

(1) wherein R is lower alkyl; R1 is methyl or ethyl, and the pharmaceutically effective acid addition salts thereof, whenever prepared by the process of claim 1 or its obvious chemical equivalent.

7. A compound of the formula:

wherein R1 is methyl or ethyl, and the pharmaceutically effective acid addition salts thereof, whenever prepared by the process of claim 3 or its obvious chemical equivalent.

8. A process according to claim 1 wherein R is methyl and R1 is methyl.

9. 12-amino-6,9,10,11-tetrahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononene, whenever prepared by the process of claim 8 or its obvious chemical eguivalent.

10. A process according to claim 1 wherein R is methyl and R1 is ethyl.

11. 12-amino-6,9,10,11-tetrahydro-3-methoxy-5-ethyl-5,10-methano-5H-benzocyclononene, whenever prepared by the process of claim 10 or its obvious chemical equivalent.

12. A process according to claim 3 wherein R1 is ethyl.

13. 12-amino-6,9,10,11-tetrahydro-5-ethyl-5,10-methano[5H]-benzocyclononen -3-ol, whenever prepared by the process of claim 12 or its obvious chemical equivalent.

14. A process according to claim 3 wherein R1 is methyl.

15. 12-amino-6,9,10,11-tetrahydro-5-methyl-5,10-methano[5H]-benzocyclononen-3-ol, whenever prepared by the process of claim 14 or its obvious chemical equivalent.

16. The process of claim 10 further comprising the resolution of the mixture of optical isomers into a diastereomeric pair or into an individual enantiomer.

17. (+)_5.alpha.-ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methano-5H-benzocyclononen-l2.beta.-amine, whenever prepared by the process of claim 16 or its obvious chemical equivalent.

18. (-)-5.alpha.-ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12.beta.-amine, whenever prepared by the process of claim 16 or its obvious chemical equivalent.

19. The process of claim 12 further comprising the resolution of the mixture of optical isomers into a diastereomeric pair or into an individual enantiomer.

20. (+)-12.beta.-amino-5.alpha.-ethyl-6,9,10,11-tetrahydro-5,10-methano-5H-benzocyclononen-3-ol, whenever prepared by the process of claim 19 or its obvious chemical equivalent.

21. (-)-12.beta.-amino-5.alpha.-ethyl-6,9,10,11-tetrahydro-5,10-methano-5H-benzocyclononen-3-ol, whenever prepared by the process of claim 19 or its obvious chemical equivalent.

22. A process for the preparation of a compound of Formula 1:

(1) or an acid addition salt thereof, which comprises selective reduction of the group =N-Y of a compound of the Formula 2:

(2) wherein R is hydrogen or lower alkyl; R1 is methyl or ethyl and Y is hydrogen, hydroxy, lower alkoxy, phen(lower)alkoxy, lower alkyl or phen(lower)alkyl to form a primary amine 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 (b) cleaving the ether group of a compound where R

is lower alkyl to form a phenolic compound, (c) resolving a mixture of optical isomers into a diastereomeric pair or into an individual enantiomer, and (d) 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.

23. The process of claim 22 wherein R is methyl and R
is methyl.

24. The process of claim 22 wherein R is methyl and is ethyl.

25. The process of claim 22 wherein R1 is ethyl and the ether group of the compound of formula 1 of claim 22 wherein R is methyl is cleaved to form a phenolic compound.

26. The process of claim 22 wherein R1 is methyl, and the ether group of the compound of formula 1 of claim 22 wherein R is methyl is cleaved to form a phenolic compound.

27. 12-amino-6,9,10,11-tetrahydro-3-methoxy-5-methyl-55, 10-methano-5H-benzocyclononene, whenever prepared by the process of claim 23 or its obvious chemical equivalent.

28. 12-amino-6,9,10,11-tetrahydro-3-methoxy-5-ethyl-5, 10-methano-5H-benzocyclononene, whenever prepared by the process of claim 24 or its obvious chemical equivalent.

29. 12-amino-6,9,10,11-tetrahydro-5-ethyl-5,10-methano-[5H]-benzocyclononen-3-ol, whenever prepared by the process of claim 25 or its obvious chemical equivalent.

30. 12-amino-6,9,10,11-tetrahydro-5-methyl-5,10-methano-[5H]-benzocyclononen-3-ol, whenever prepared by the process of claim 26 or its obvious chemical equivalent.

31. The process of claim 22 wherein R is methyl, R1 is ethyl, and the mixture of optical isomers is resolved into a diastereomeric pair or into an individual enantiomer.

32. The process of claim 25 wherein the mixture of optical isomers is resolved into a diastereomeric pair or into an individual enantiomer.

33. (+)-5.alpha.-ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12.beta.-amine, whenever prepared by the process of claim 31 or its obvious chemical equivalent.

34. (-)-5.alpha.-ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12.beta.-amine, whenever prepared by the process of claim 31 or its obvious chemical equivalent.

35. (-)-12.beta.-amino-5.alpha.-ethyl-6,9,10,11-tetrahydro-5,10-methano-5H-benzocyclononen-3-ol, whenever prepared by the process of claim 32 or its obvious chemical equivalent.

36. (-)-12.beta.-amino-5.alpha.-ethyl-6,9,10,11-tetrahydro-5,10-methano-5H-benzocyclononen-3-ol, whenever prepared by the process of claim 32 or its obvious chemical equivalent.

37. A compound of the formula (8) or an acid addition salt thereof, wherein R is hydrogen or lower alkyl and R1 is methyl or ethyl whenever prepared by the process of claim 22 or its obvious chemical equivalent.

38. A process as defined in claim 22 wherein there is previously formed a ketone of the Formula 4:

(4) wherein R is hydrogen or lower alkyl and R1 is methyl or ethyl; by a process which comprises treating a compound of the Formula 5: - (5) where R is lower alkyl, R1 is methyl or ethyl, 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 and if a ketone in which R is hydrogen is desired, cleaving the ether linkage to form the phenolic compound.

39. A process as defined in claim 38 wherein there is previously formed a compound of the Formula 5:

(5) where R is lower alkyl, R1 is methyl or ethyl, and X is chlorine or bromine by a process which comprises treating a compound of the Formula 6:

(6) wherein R is lower alkyl and R1 is methyl or ethyl, with a cis compound of the formula:

(7) where X is chlorine or bromine in the presence of a strong base, preferably an alkali metal alkoxide, hydride or amide.

CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE:

40. A process for the preparation of a compound of the formula:

(8) wherein R and R1 are each lower alkyl, which comprises:
(a) treating a ketone of the formula:

wherein R and R1 are as defined hereinabove with cis-1,4-di-chloro-, 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:

wherein R and R1 are as defined hereinabove 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:

wherein R and R1 are as defined hereinabove;
(c) treating said tricyclic ketone with a compound of the formula H2NY wherein Y is hydrogen, hydroxy, lower alkoxy or phen(lower)alkoxy to produce an imino compound of the formula:

wherein R, R1 and Y are as defined hereinabove; and (d) selectively reducing the imino group of said imino compound

41. A process for the production of a compound of the formula:
(11 ) wherein R1 is lower alkyl, which comprises:
(a) preparing, by the method of claim 40, a compound of the formula:

(8) wherein R is lower alkyl or phen(lower)alkyl and R1 is as defined hereinabove; and (b) cleaving the ether function.

42. A compound of the formula:

(8) wherein R and R1 are each lower alkyl, and the pharmaceutically effective acid addition salts thereof, whenever prepared by the.
process of claim 40 or its obvious chemical equivalent.

43. A compound of the formula:

(11 ) wherein R1 is lower alkyl, and the pharmaceutically effective acid addition salts thereof, whenever prepared by the process of claim 41 or its obvious chemical equivalent.

44. A process for the preparation of a compound of Formula (11 ) or an acid addition salt thereof, which comprises selective reduction of the group =N-Y of a compound of the Formula 2 (2) wherein R is hydrogen or lower alkyl, R1 is lower alkyl and Y
is hydrogen, hydroxy, lower alkoxy, phen(lower)alkoxy, lower alkyl or phen(lower)alkyl to form a primary amine 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, (b) cleaving the ether group of a compound where R is lower alkyl to form a phenolic compound (c) resolving a mixture of optical isomers into a diastereomeric pair or into an individual enantiomer, and (d) converting a compound of Formula 11 into an acid addition salt thereof or converting an acid addition salt form of compound of Formula 11 into the free amine.

45. A process as defined in claim 44 wherein there is previously formed a ketone of the Formula 4:

(4) wherein R is hydrogen or lower alkyl and R1 is lower alkyl;
by a process which comprises treating a compound of the Formula 5:

(5) where R and R1 are each lower alkyl, 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 and if a ketone in which R is hydrogen is desired, cleaving the ether linkage to form the phenolic compound.

46. A process as defined in claim 45 wherein there is previously formed a compound of the Formula 5:

(5) where R and R1 are each lower alkyl, and X is chlorine or bromine by a process which comprises treating a compound of the Formula 6:

(6) wherein R and R1 are each lower alkyl, with a cis compound of the formula:

(7) where X is chlorine or bromine in the presence of a strong base, preferably an alkali metal alkoxide, hydride or amide.