CH617664A5 - Process for the preparation of benzobicycloalkeneamines and related compounds - Google Patents

Abstract

Preparation of a compound of formula: <IMAGE> by reaction of a 1-R-7-RO-2-tetralone with a 1,4-dihalo-2-butene compound, to obtain the corresponding 1,1'-R-halobutenyl substituted tetralone. This compound is then cyclised to produce, by closing of the butanyl ring in position 3, the corresponding tricyclic ketone. By reaction with an amine derivative H2N-Y, the ketone group is converted to an imino group which is then reduced to an NH2 group. The group OR can be converted to an OH group and the NH2 group can be converted to a secondary or tertiary amino group. A mixture of optical isomers can be separated and acid addition salts can be prepared. These compounds are useful as analgesic agents and as intermediates for the preparation of other analgesic agents.

Description

The invention relates to the preparation of benzobicyclo-alkene- and -alkane-amines which are useful as analgesic agents, as well as as products involved in the preparation of other analgesic agents, namely benzobicyclo-alkane-amines. The invention relates more particularly to the preparation of 6,9,10,11 -tetrahydro-5,10-methano-5H-benzo-cyclononén-12-amines, as well as to their use in other methods of preparation 6,7,8,9,10,11-hexahydro-5,10-methano-5H-benzocyclononén-12-amines.

The state of the art is illustrated by patent of the United States of America No. 3836670 in which similar compounds are described, the preparation of which is still different from that according to the present invention.

The invention generally encompasses the preparation of new chemical compounds corresponding to formula (la):

RO

aa)

NR ~ R

wherein R 'represents hydrogen, lower alkyl or phenylalkyl; R1 represents methyl, ethyl or lower alkenyl; and R2 and R3 are independently selected from the group comprising hydrogen, lower alkyls, lower alkenyls, lower alkynyls and lower phenylalkyls, the invention also including the acid addition salts of these compounds, preferably acid addition salts effective in pharmacies. The invention also encompasses the preparation of certain derivatives of (la) with non-aromatic saturation. The new compounds corresponding to formula (la) in general, in the form of the acid salt, are crystalline solids which are essentially insoluble in ether and are soluble in polar hydroxyl solvents, such as methanol and ethanol . Examination of compounds produced according to the method described below reveals, during infrared and resonance spectrographic analyzes. nuclear magnetic, spectra confirming the molecular structures given above.

The compounds of formula (la) and their acid addition salts are also useful in the synthesis of benzobicycloalkane-amines, which are analgesic agents, and in addition forms of primary amines and secondary amines of the compounds of formula (I) and their pharmaceutically effective acid addition salts exert analgesic effects on test animals.

The method according to the invention is defined in claim 1; the primary amines of formula are obtained:

RO

NH,

in which R represents a lower alkyl or phenylalkyl radical, and R1 represents a methyl, ethyl or lower alkenyl group. If desired, one or more of the following phases can be followed, namely:

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a) the conversion of a primary amine into a secondary or tertiary imine in accordance with formula (la);

b) separating the ether group (R is lower alkyl or phenyl lower alkyl) to form a phenolic compound (R = H);

c) splitting a mixture of optical isomers into a diastereoisomeric pair or into an individual enantiomer, and d) converting a compound of formula (I) into an acid addition salt or the conversion of an acid addition salt form of the compound of formula (I) to the free amine.

When a primary amine of formula (I) has been formed in which R2 and R3 represent hydrogen, or an acid addition salt of such an amine, such a product can be converted into a secondary amine or tertiary using traditional methods. These 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 tertiary dime-thylamino derivative by means of formaldehyde and formic acid. The primary amine can also be converted into a secondary amine in which R2 is hydrogen and R3 is lower alkyl, lower alkenyl, lower alkynyl or lower phenylalkyl, by reaction with a halo compound of the general formula;

Hai — R3

wherein Hai is a halogen, such as chlorine or bromine or iodine, and R3 is lower alkyl, lower alkenyl, lower alkynyl or lower phenylalkyl, preferably in the presence of an organic base. Similarly, a secondary amine in which R2 is hydrogen and R3 can be converted from lower alkyl, lower alkenyl, lower alkynyl or phenylalkyl can be converted to a tertiary amine in which R2 and R3 are both selected. independently from lower alkyls, lower alkenyls, lower alkynyls or lower phenylalkyls, by reaction with a lower alkyl halide, a lower alkenyl halide, a lower alkynyl halide or a lower phenylalkyl halide.

If desired, a compound of formula (I) or an acid addition salt of such a compound, where R represents lower alkyl or lower phenylalkyl, may be subjected to separation of the ether bond to form a phenolic compound where R represents hydrogen. Examples of separating agents allowing fragmentation of the ethers are Lewis acids, for example aluminum chloride or boron tribromide, and hydrochloric acids, for example hydrobromic acid.

The compounds of formula (I) have the property of an optical isomer and mixtures of the optical isomers can be split into the individual isomers. The separation of the diastereoisomeric pairs and their splitting into enantiomers can, if desired, be carried out by well known methods.

The new compounds of formula (I) can be isolated as such or in the form of an acid addition salt. The acid addition salt forms can be prepared by adding an acid to the compound of formula (I). As the acids from which the salt can be derived, hydrochloric, maleic, citric, acetic, benzoic or other pharmacologically acceptable acids can be used. The addition of the acid is preferably carried out in an alcoholic solution. The acid addition salts can be converted to the amine itself in a conventional manner by the addition of a base.

The compounds corresponding to formula (2):

(Formula at the top of the next column)

in which R represents hydrogen, lower alkyl or lower phenylalkyl, R1 is methyl, ethyl or a

(2)

io lower alkenyl, and Y represents hydrogen or a hydroxy radical, lower alkoxy, lower phenylalkoxy, lower alkyl, or lower phenylalkyl, are new compounds resulting from the penultimate stage of the process according to the invention. The invention therefore provides for the intermediate preparation of a new compound i5 corresponding to formula (2), this process comprising the treatment of a compound corresponding to formula (4):

(4)

In which R and R1 have the definition given previously for the formula (2), with a compound of the formula H2NY, where Y has the previous definition.

New are the compounds of formula (4) above, wherein R represents hydrogen, lower alkyl or lower phenylalkyl and R1 represents methyl, ethyl or lower alkenyl. The new compounds of formula (4) are, generally, high boiling liquids or crystalline solids, which are essentially insoluble in water and are soluble in benzene, alkanols 35 lower, like methanol, ketone solvents like acetone and methyl ethyl ketone, etc. An examination of the compounds produced according to the method described below reveals, during infrared spectrographic analyzes and nuclear magnetic resonance, spectra confirming the molecular structure given above 40 for tricyclic ketones.

Another intermediate compound in the preparation process is a tricyclic ketone of formula (4), obtained by the treatment of a compound of formula (5):

45

50 RO

(5)

in which R is lower alkyl or lower phenylalkyl, R1 is methyl, ethyl or lower alkenyl, and X represents chlorine or bromine, with a strong base, preferably an alcoholate, a hydride or an amide of alkali metal, 60 to produce a tricyclic ketone of formula (4) in which R is lower alkyl or phenylalkyl and, if desired a ketone in which R represents hydrogen, separation of the ether bond for form the phenolic compound. The strong base used for the reaction with the compound of 65 of formula (5) is suitably used in excess in a suitable solvent. The strong base can be, for example, potassium t-butoxide in t-butanol, or sodium hydride or sodium amide in dimethylformamide.

5

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When an ether bond has to be separated, this separation can be carried out in a known manner, for example using a Lewis acid.

The compounds corresponding to formula (5) are new products. They are obtained during the process according to the invention by the treatment of a compound of formula (6):

, 1

(6)

in which R is lower alkyl or lower phenylalkyl and R1 is methyl, ethyl or lower alkenyl, with a compound eis of the formula:

H

H

\ /

/

XCHn

CH0X

in which R is lower alkyl or lower phenylalkyl and R1 is methyl, ethyl or lower alkenyl, by a sequence of reactions which comprises:

a) the treatment of a ketone of the formula:

, 1

in which R and R1 have the definition given above for formula (6) with cw-1,4-dichloro- or 1,4-dibromo-2-butene in the presence of an excess of an alcoholate, a hydride or an alkali metal amide to form an addition compound of the formula:

ll CH2CH = CHCH2X

(7)

in which X represents chlorine or bromine in the presence of a strong base, preferably an alcoholate, a hydride or an amide of an alkali metal. The strong base is preferably used in an excess amount in a suitable solvent. The product (5) obtained can be used directly to form the tricyclic ketone (4) without isolating the adduct (5).

The starting materials for the preparation of the adduct (5) are known products or can be obtained by known methods. In particular, eis-1,4-dichloro-2-butene and cw-1,4-dibromo-2-butene are known compounds. The compounds of formula (6), namely 1-alkyl- or 1-alkenyltetralones, can be prepared by methods described below.

It will be understood that by combining the methods described above, it is possible to synthesize the new compounds of formula (I) and also the compounds of formula (3). By way of example, the following syntheses may be mentioned in accordance with the invention.

During the process of the invention, a compound corresponding to the formula is therefore prepared:

R1 ^ ^

(6)

(5)

= 0

in which R and R1 have the definition given above for formula (6) and X represents a chloro or bromo radical; b) the treatment of this addition compound with a second excess of alkali metal alcoholate, hydride or amide to produce a tricyclic ketone of the formula:

or

25

(4)

in which R and R1 have the definition given previously for formula (6);

c) treating this tricyclic ketone with a compound of the formula H2NY1, wherein Y1 is hydrogen, hydroxy, lower alkoxy or phenylalkoxy lower, to produce an imino compound of the formula:

(10)

in which R and R1 have the definition given previously for the formula (6) and Y1 has the definition above, and d) the selective reduction of the imino group of the abovementioned imino compound.

In the description of the process for the preparation of a particular embodiment of the invention, reference will be made to the reaction scheme represented in the drawing in which the compounds are designated by Roman numerals. This diagram illustrates the synthesis of various particular embodiments of formula (I), namely 12-amino-5-ethyl-6,9,10, ll-tetrahydro-5,10-methano- [5H] -benzocyclononén -3-ol (X) and 5-ethyl-6,9,10, ll-tetrahydro-3-methoxy-5,10-methano- [5H] -benzocyclononen-12-amine (IX), and a form of particular embodiment of formula (4), namely 5-ethyl-6,7,10, ll-tetrahydro-3-methoxy-5,10-methano- [5H] -benzocyclononén-12-one (III). This diagram also illustrates the use of the process which is the subject of the invention for the preparation of 6,7,8,9,10,1 l-hexahydro-5,10-methano- [5H] -benzo-cyclononén- Particular 12-amines, namely 5-ethyl-6,7,8,9,10, ll-hexahydro-3-methoxy-5,10-methano- [5H] -benzo-cyclonen-12-amine (VIII) and 12-amino-5-ethyl-6,7,8,9,10, ll-hexahydro-5,10-methano- [5H] -benzocyclononén-3-ol (XI).

1-Ethyl-7-methoxy-2-tetralone (III) and an excess of cw-1,4-dichloro-2-butene (IV) are treated suitably at room temperature in an inert atmosphere with an slight excess of 1 equivalent of a strong base, more particularly potassium t-butoxide, over a period of approximately 12 to approximately 24 hours, preferably approximately 18 hours, to obtain the compound (V). The isolation of compound (V) is not necessary and provision is made for

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treatment of the reaction mixture containing it with an additional excess of the strong base, followed by a heating period, preferably for 6 h at the reflux temperature of the solvent used, an operation which is in turn followed by an additional reaction period allowed to develop at room temperature for an additional 16 hours. The exact reaction times and temperatures are obviously not critical. The strong base to be used, as well as the appropriate solvent, are also not particularly critical and those skilled in the art may consider many suitable combinations, for example potassium t-butoxide in t-butanol and sodium hydride or amide in dimethylformamide; if potassium t-butoxide is the strong base employed, t-butanol is a particularly suitable solvent. The compound VI thus produced is then isolated by conventional methods. Oxime VII is then prepared by treatment of compound VI with hydroxylamine in an inert solvent, for example methanol, initially at an elevated temperature, preferably at the reflux temperature of the solvent used, over a short period of time. time, normally 6 h, followed by a longer period, for example 18 h, at room temperature. Compound VII is recovered by conventional means. This compound VII can, if desired, be reduced directly to compound VIII; catalytic hydrogenation is a particularly convenient method for this transformation. Separation of compound VIII to produce compound IX can, if desired, be carried out in the usual manner by treatment with hydrochloric acids, such as hydrobromic acid or hydroiodic acid, in hot aqueous solution. Alternatively, if desired, the oximino function of compound VII can be selectively reduced, the Bouveault-Blanc method being especially suitable for producing compound IX. If desired, the latter can be reduced to produce compound VIII. Catalytic hydrogenation is particularly suitable for this reduction. Compound IX can be cleaved if desired, suitably with a Lewis acid, such as boron tribromide, to produce compound X. If desired, the latter can be reduced to produce compound XI. Catalytic hydrogenation is suitable for this reduction. The isolation of the compounds Vili, IX, X and XI can be carried out by conventional means, if desired.

Although the process of the invention has been described with reference to the diagram illustrating its application to 1-ethyl-7-methoxy-2-tetralone, it will be obvious that this process is also applicable to other tetralones bearing in positions 1 and 7 the various substituents envisaged in the context of the invention.

The preparation of the variously substituted secondary and tertiary amines envisaged in the context of the invention is also obvious and conventional methods are well known to specialists. By way of example, the tertiary dimethylamino derivatives can be prepared by means of a Leuchart-Wallach reaction using formic acid and formaldehyde.

One skilled in the art will also understand that the ether bond of compound VI can be separated in a similar manner to the separation of the ether bond of compound IX. The phenolic compound thus produced will obviously be the equivalent of compound VI for the needs of other transformations. It is obvious that the other tricyclic ketones of formula (4) envisaged within the framework of the invention, which comprise an ether in position 3, can also be divided or subjected to separation to give the corresponding phenolic compound which will obviously be the total equivalent of non-phenolic compounds for the purpose of other reactions.

The starting materials for the implementation of the invention, namely 1-alkyl- or 1-alkenyl-2-tetralones, can be prepared using the 2-tetralones already available, by a well-known alkylation reaction , as described in particular by Stork and Schulenberg in "Journal of the American Chemical Society", 84, 284, (1962). The tetralones are treated with pyrrolidine in an inert solvent, such as benzene, and reacted with a suitable lower alkyl or lower alkenyl halide in an inert solvent, such as benzene or dioxane, high temperatures, preferably at the reflux temperature of the solvent used. They can also be prepared using a suitable commercially available 1-tetralone which can be treated as described by Howell and Taylor in "Journal of the Chemical Society", 1958,1249, with a Grignard reagent, prepared from an appropriate lower alkyl or lower alkenyl halide, and with oxidation of the resulting 1-substituted dihydro-naphthalene with a peracid.

Numerous tetralones are available on the market, and synthetic methods for non-available tetralones can easily be found in the literature. As examples, the synthesis of a-tetralone is described in "Organic Synthesis", collective, volume IV, p. 898; the synthesis of p-tetralone is described in the same work at p. 903, and a general synthesis of P-tetralones is described by Nagata et al. In Dutch patent No. 67/09534 of January 10, 1968.

It will be obvious to specialists in this chemical field that the ketones of formula (4) will be produced in the form of racemic mixtures, and that a reduction of their oximes will give the amines of formula (I) in the form of diastereoisomers. The separation of the diastereoisomeric pairs and their splitting into enantiomers can be carried out, if desired, by well known methods. Diastereoisomers, enantiomers and mixtures thereof are also included within the scope of the invention. The analgesic activity of the compounds of formula (I) and of their acid addition salts suitable for pharmacy can be demonstrated by following a variant of the test method described by D'Amour and Smith in “Journal of Pharmacology , 72, 74 (1941), which is an accepted trial for analgesic agents.

In this trial, the rats are administered the compound orally, in the peritoneum and intramuscularly, and the time required for a response to a pain stimulus caused by a high intensity light beam is measured focusing on the tail. The compounds of formula (I) and their acid addition salts have analgesic activity on rats at doses greater than 1.56 mg / kg when introduced into the peritoneum, in particular doses of 6, 25 to 25.0 mg / kg.

The 6,7,8,9,10,11-hexahydro-5,10-methano-5H-benzocyclo-nonén-12-amines, which are the products of interest in a number of the various processes of the invention, create also analgesic activity in warm-blooded animals and they are described in Belgian Patent No. 776173.

When the compounds of formula (I) and their acid addition salts are used as analgesic agents, they can be administered to warm-blooded animals, for example to mice, rats, rabbits, monkeys, etc. ., alone or in combination with pharmacologically acceptable supports or vehicles.

The dosage used during the administration of the compounds obtained according to the invention will vary with the form of administration and the compound chosen. In addition, it will vary with the particular subject being treated. Generally, the treatment is started with small doses, substantially less than the optimal dose of the compound. Then the dosage is increased in small amounts until the optimal effect is reached under the particular circumstances. Generally, the new compounds are most advantageously administered at a concentration level which will generally give effective results without causing any harmful side effects.

As used in the present case, the expression lower alkyl denotes a saturated hydrocarbon radical, comprising straight chain radicals and branched radicals, comprising

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1 to 6 carbon atoms, among which mention may be made of methyl, propyl and isobutyl. The expression lower alkenyl designates an unsaturated hydrocarbon radical, including straight chain radicals and branched radicals, containing 3 to 5 carbon atoms, among which there may be mentioned, by way of example, allyl radicals, 2- butenyl, 3-methyl-2-butenyl and 2-pentenyl. The expression lower phenylalkyl designates a lower alkyl radical as defined above, substituted in a terminal position by a phenyl radical or by a phenyl radical itself substituted by a lower alkyl or a lower alkyloxy, and mention may be made by way of examples are benzyl, phenethyl, o-, m- and p-anisyl, veratryl, and o-, m- and p-xylyl radicals.

The following examples further illustrate the invention.

Example I:

6,9,10,1 l-Tetrahydro-3-methoxy-5-methyl-5,10-methano-5H-

benzocyclononén-12-one.

Under a nitrogen atmosphere, a solution of 1-methyl-7-methoxy-2-tetralone (40 g; 0.21 M) in 100 ml of t-butanol is added dropwise to a freshly prepared solution of t potassium potassium butylate (9.8 g; 0.25 M potassium in 400 ml t-butanol). The mixture is stirred at room temperature for 1 h at the end of the addition, then it is transferred under nitrogen to a tap funnel, and it is added dropwise to a solution of eis-1,4-dichloro -2-butene (53 g; 0.42 M) in t-butanol, while stirring under nitrogen. The stirring is left to continue for approximately 18 h, after addition of 1 g of potassium iodide, at room temperature. An additional quantity of a fresh solution of potassium t-butoxide (15 g; 0.38 M potassium in 400 ml of t-butanol) is then added dropwise, and the mixture is refluxed for 6 h at the end of the addition. After the reflux period, the addition is continued at room temperature for about 16 h. The reaction mixture is then poured into water (about 41) and the organic phase is extracted into benzene. The benzene solution is washed twice with water, dried over magnesium sulfate, and the solvent is separated in vacuo to give a crude oil (57 g). Distillation of the crude oil gives a product (36 g) with a boiling point of 155-165 ° C (0.5 mm) which is crystallized from hot heptane (melting point 79-81 ° C).

Example II:

Oxime of 6,9,10,1 l-tetrahydro-3-methoxy-5 methyl-5,10-

methano-5H-benzocyclononén-12-one.

A clear solution of sodium acetate (23 g) is mixed

in 15 ml of methanol, with a clear solution of hydroxylamine hydrochloride (19.5 g) in 200 ml of methanol, and the resulting precipitate of sodium chloride is separated by filtration. To this mixture is added a solution of 6,9,10,11-tetrahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononén-12-one (13.5 g) in methanol ( 50 ml). When the addition is complete, the reaction mixture is refluxed for about 4 h, and the stirring is allowed to develop for an additional 16 h. The solvents are then separated under vacuum and the rest is transformed into a paste with water to finally give a solid which is separated by filtration, treated with water and dried to form a product, 14.2 g, point of melting at 122-125 ° C. Recrystallization from isopropanol gives the product mentioned in the heading, 11.7 g, melting point of 124-126 ° C.

Example III:

6,7,8,9,10,1 l-Hexahydro-3-methoxy-5a-methyl-5,10-methano-

5H-benzocyclononén-12 $ -amine.

6.9,10.1 l-tetrahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one (5 g), ethanol (150 g) are shaken ml), concentrated ammonium hydroxide (30 ml) and Raney nickel (2 teaspoons) with hydrogen at a pressure of the order of 2.8 kg / cm2 for 5 h at temperature ambient. The catalyst is filtered off and the solvent is removed in vacuo. The residual oil is distributed between ether and water. Separation of the ethereal layer, drying over magnesium sulfate and separation of the ether under vacuum gives a crude product, 4.5 g.

The treatment of an ethereal solution of the crude product with anhydrous hydrochloric acid gives a precipitate, 3.5 g, melting point of 265-272 ° C. Recrystallization from hot water gives the product mentioned in section as hydrochloride salt, 1.6 g, melting point 301-303 ° C.

Example IV:

5-Ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methano-5H-benzocyclononén-12-one. .

By following a process analogous to that used in Example I for the preparation of 6,9,10,11-tetrahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononén-12-one, we obtains, from l-ethyl-7-methoxy-2-tetralone (20.4 g) and cw-1,4-dichloro-2-butene (25 g), 17.8 g of the product in heading, PE 150-185 ° C (0.4 mm).

Example V:

5-ethyl-6,9,10, llime-tetrahydro-3-methoxy-5,10-methano-5H-benzocyclononén-12-one oxime.

By following a process analogous to that employed in Example II for the preparation of the oxime of 6,9,10,11-tetra-hydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononén -12-one, from 5-ethyl-6,9,10, ll-tetrahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12-one (16.0 g) is obtained, and a clarified mixture of sodium acetate (25.5 g) and hydroxylamine hydrochloride (22 g) in 200 ml of methanol, 10.3 g of the product mentioned in the section, melting point 150-153 ° vs.

Example VI:

5a-Ethyl-6,7,8,9,10, ll-hexahydro-3-methoxy-5,] 0-methano-5H-benzocyclononén-12fi-amine.

By following a process analogous to that used in Example III for the preparation of 6,7,8,9,10,1 l-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononén- 12-amine is obtained from 5-ethyl-6,9,10, ll-tetrahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12-one oxime (3.0 g ), 1.4 g of the hydrochloride salt of the product mentioned in the section, melting point of 247-250 ° C.

Example VII:

6,9,10,1 l-Tetrahydro-3-methoxy-5 <x-methyl-5,10-tnéthanO-5H-benzocyclononén-12ft-amine.

Clean sodium pellets (4.4 g) are added over a period of about 90 minutes to a reflux solution, during stirring, of 6,9,10, ll-tetrahydro-3 oxime. -methoxy-5-methyl-5,10-methano-5H-benzocyclononén-l 2-one (2.5 g) in 2.5 ml of dry ethanol, while maintaining a layer of nitrogen. At the end of the addition, reflux and stirring are continued for approximately 1 h. The reaction is cooled to 20 ° C and diluted with 25 ml of dry ethanol. Stirring is continued until the sodium fragments are no longer visible. The solution is again cooled to 20 ° C. and a mixture of water and ice (about 200 ml) is added to it. The ethanol is separated by concentration in vacuo and the remaining aqueous solution is shared with ether. The ethereal fraction is washed with saline, dried over sodium sulfate and concentrated in vacuo to give an oil. This oil is taken up in ether and treated with an excess of dry hydrochloric acid to form a product, 2.07 g, point of

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melting at 287-289 ° C (decomposition). Recrystallization of this product from methanol / water acidified with concentrated hydrochloric acid gives the hydrochloride salt of the product mentioned in the section, 1.56 g, melting point 300-302 ° C.

Analysis for C16H22CINO:

Calculated: C 68.68 H 7.93 N5.01 Cl 12.67

Found: C 68.81 H 8.23 N5.21 Cl 12.38

Resonance analysis: signals at 5 = 5.55, 5.1 (triplets, total nuclear magnetic: 2 protons) ppm.

Example VIII:

5a.-Ethyl-6,9,10, ll-tetrahydro-3-methoxy-5,10-methano-5H-benzocyclononén-12 $ -amine.

By following a process analogous to that used in Example VII for the preparation of 6,9,10,1 l-tetrahydro-3-methoxy-5a-methyl-5,10-methano-5H-benzocyclononén-12ß-amine , from 5-ethyl-6,9,10, ll-tetrahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12-one (3.8 g), 1.76 g of the product mentioned in the section, melting point of 77-78 ° C, as well as a second harvest, 0.6 g, melting point of 74-76 ° C.

Analysis for C17H23ON:

Calculated: C 79.33 H 9.01 N5.44

Found: C 79.36 H 9.35 N5.38

NMR analysis: signals at 8 = 5.2 (wide, multiplet) ppm.

Mass spectrum:

Calculated: m / e 257.0

Found: m / e 257.0

The material of the second crop of the free base, as well as a sufficient amount of the material of the first crop to form a total of about 0.7 g is dissolved in ether and treated with an excess of hydrochloric gas dry to give the hydrochloride salt of the above-mentioned product, 0.98 g, melting point 285-286 ° C.

Analysis for C17H24CION:

Calculated: C 69.49 H 8.23 N4.77 Cl 12.07

Found: C 69.14 H 8.66 N4.78 Cl 12.32

Example IX:

12Ç> -Amino-5a-ethyl-6,9,10,11 -tetrahydro-5,10-methano-SH-benzocyclononén-3-ol.

A solution of 5-ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12-amine (3.0 g) is cooled to -20 ° C. dry methylene chloride (100 ml), while maintaining a nitrogen blanket, and a solution of boron tribromide (6.7 g) in dry methylene chloride is added over a period of 30 min, while maintaining the temperature around - 20 ° C and stirring. When the addition is complete, the reaction product is allowed to warm to room temperature and stirring is continued under nitrogen for about 16 h. After the reaction mixture has cooled to 0 ° C., 150 ml of cold water are added and stirring is continued for approximately 1 h. The layers formed at rest are separated and the aqueous layer is made basic with concentrated ammonium hydroxide. Filtration is used to separate a product, 2.1 g, melting point 178-186 ° C. Recrystallization from methanol gives the product mentioned in the heading, 0.7 g, melting point 216-218 ° C .

Example X:

N, N, 5a.-Trimethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methano-5H-benzocyclononén-12fi-amine.

6,9,10,1 l-tetrahydro-3-methoxy-5a-methyl- are dissolved

5,10-methano-5H-benzocyclononén-12p-amine (5 g) in 90% formic acid (5.2 g). 40% aqueous formaldehyde (4.5 ml) is added and the stirred solution is slowly heated. When the temperature of the solution reaches 40 ° C, a significant evolution of CO2 begins. When the reaction temperature begins to drop, the external heating is resumed and the reaction is maintained at 90 ° C for 8 h. After cooling, the reaction mixture is concentrated in vacuo. The residue is dissolved in water, an excess of a dilute sodium hydroxide solution is added and the mixture is partitioned with ether. The ethereal portion is washed with saline, dried over sodium sulfate and concentrated in vacuo to form an oil, 4.8 g. This oil is dissolved in ethanol and treated with an excess of hydrochloric gas. At rest, the hydrochloride of the product mentioned in the section separates in the form of crystals, 3.5 g, melting point of 228-230 ° C.

Analysis for C18H26CINO:

Calculated: C 70.22 H 8.51 N4.55 Cl 11.52

Found: C 70.31 H 8.68 N4.34 Cl 11.84

Example XI:

N, N-Dimethyl-6,9,10,11 -tetrahydro-3-methoxy-5i-ethyl-5,10-methano-5H-benzocyclononén-12ft-amine.

By following a process analogous to that described in Example X for the synthesis of N, N-5a-trimethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methano-5H-benzocyclononén- 12p-amine, from 6,9,10,11-tetrahydro-3-methoxy-5a-ethyl-5,10-methano-5H-benzocyclononen-12p-amine, the product in column which is converted by traditional means in its hydrochloride, melting point 236-237 ° C.

Analysis for C19H28NOCI:

Calculated: C 70.89 H 8.77 N4.35 Cl 11.02

Found: C 70.90 H 8.97 N 4.31 Cl 10.70

Example XII:

5a-Ethyl-6,9,10,11-tetrahydro-3-methoxy-N-methyl-5,10-methano-5H-benzocyclononén-12 $ -amine.

A solution of 5 <x-ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12ß-amine (6.5 g; 0.25 M) and Methyl iodide (4.0 g) in acetone (200 ml) is treated at reflux over a period of 12 h. The solution is cooled to ambient temperature and the iodhydrate of the product mentioned in the heading is separated in the form of a white precipitate by filtration (5.3 g), melting point 251-254 ° C.

A distribution of the hydroiodide between ether and a dilute solution of sodium hydroxide, followed by drying the ethereal solution over MgSO4 and treatment with an excess of hydrochloric acid, gives the hydrochloride of the product cited in rubric in the form of a white precipitate which is recovered by filtration and which is recrystallized from ethanol, 2.6 g, melting point 279-281 ° C.

Analysis for CisH ^ ClNO-% H2O:

Calculated: C 69.21 H 8.39 N4.48 Found: C 69.53 H 8.64 N4.42

Example XIII:

Duplication of 5a.-ethyl-6,9,10, ll-tetrahydro-3-methoxy-5,10-methano-5H-benzocyclononén-12fi-amine.

A. To a solution of 50 g of d-tartaric acid in 1.51 of methanol is added a solution of 76.5 g of 5a-ethyl-6,9,10, 1 1-tetrahydro-3-methoxy- 5,10-methano-5H-benzocyclononén-12p-amine in methanol. The resulting solution is diluted to 3.01 and allowed to stand overnight. Filtration gives 56 g of a salt with a melting point of 199-202 ° C (decomposition).

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Three recrystallizations of this salt in methanol give 28.4 g of a salt with a melting point of 209-211 ° C (decomposition) and having a value [a] ^ 5 = - 47.6 °.

The salt is converted to the free base by separation with dilute sodium hydroxide and ether. The ethereal portion, after drying, is concentrated to give 17 g of base which crystallizes on standing, melting point of 50-53 ° C, [oc] ^ j = —85.4 °.

Convert a 4 g portion of the base to its hydrochloride in ether. Recrystallization of the salt from ether-ethanol gives 4.0 g of product with a melting point of 272-275 ° C, [affi = -69.6 °.

Analysis for C17H24NOCI:

Calculated: C 69.49 H 8.23 N4.77

Found: C 69.33 H 8.51 N 4.63

B. The mother liquors from the recrystallization of the d-tartrate salt from part A above are combined and concentrated. The residue is converted to the free base by partitioning between ether and dilute sodium hydroxide. The ethereal 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 (<) - tartaric acid in methanol. The resulting solution is diluted to 2.8 L and left to stand overnight. Filtration gives 55 g of salt with a melting point of 200-205 ° C. Two recrystallizations of this salt in methanol give 31.4 g of salt with a melting point of 210-2110 C (decomposition) and of a. value [ot] ^ = + 47.7 °.

The salt is converted to the base in the same way as the previous rotamer (-) to obtain 19 g crystallizing at rest, melting point 48-51 ° C, [a] ^ j = + 84.3 °.

A 4 g sample is converted to the hydrochloride which, upon recrystallization from ethanol-ether, has a melting point of 260-265 ° C, ["] $ = + 69.3 °.

Analysis for C17H24NOCI:

Calculated: C 69.49 H 8.23 N4.77

Found: C 69.60 H 8.59 N 4.69

Example XIV:

(+) - $ 12 -Amino-5oi-ethyl-6,9,10, ll-tetrahydro-5,10-methano-

5H-benzocyclononén-3-ol.

By following a process analogous to that described in

617,664

Example IX for the preparation of 12ß-amino-5a-6thyl-6,9,10,1 l-tetrahydro-5,10-methano-5H-benzocyclononén-3-ol, obtained from 15 g of ( +) 5a-ethyl-6,9,10, ll-tetrahydro-3-methoxy-5,10-methano-5H-benzocyclononén-12p-amine, 11.4 g of solid base with a melting point of 167- 172 ° C. This base is converted to its hydrochloride salt in methanol-ether. Recrystallization of the salt from ethanol-ether gives 12.0 g of the (+) salt with a melting point of 261-263 ° C, ["] $ = + 83.0 °.

Analysis for C16H22NOCI:

Calculated: C 68.68 H 7.93 N5.01 Found: C 68.53 H 8.25 N4.89

Example XV:

(-) -12 $ -Amino-5a-ethyl-6,9,10,11 -tetrahydro-5,10-methano-5H-benzocyclononén-3-ol.

By following a process analogous to that described in Example IX for the preparation of 12P-amino-5a-ethyl-6,9,10,1 l-tetrahydro-5,10-methano-5H-benzocyclononén-3-ol, 13 g of (-) - 5ac-ethyl-6,9,10, l 1-tetrahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12P-amine are obtained from 9.0 g of solid base. This base is converted to its hydrochloride salt in methanol-ether. Recrystallization of the salt from ethanol-ether gives 7.5 g of the salt (-) with a melting point of 260-262 ° C, [<x] $ = -82.8 °.

Analysis for C16H22NOCI:

Calculated: C 68.68 H 7.93 N5.06 Found: C 68.80 H 8.23 N4.91

Example XVI:

12fi-Amino-5a.-methyl-6,9,10,1 l-tetrahydro-5,10-methano-5H-benzocyclononén-3-ol.

By following a process analogous to that described in Example IX for the preparation of 12ß-amino-5a-Othyl-6,9,10,1 l-tetrahydro-5,10-methano-5H-benzocyclononén-3-ol, 0.25 g of the salt is obtained from 2.0 g of 6.9,10.1 l-tetrahydro-3-methoxy-5Ç-methyl-5,10-methano-5H-benzocyclononén-12p-amino hydrochloride addition of the product mentioned in the heading in the form of a solvate in ethanol, melting point of 180 ° C. (decomposition).

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1 sheet of drawings

Claims (18)

617,664 CLAIMS 1. Process for the preparation of a compound of formula: RO NH, in which R represents a lower alkyl or phenyl-lower alkyl radical, and R1 represents a methyl, ethyl or lower alkenyl group, characterized in that: a) reacting a ketone of formula: in which R and R1 have the given meaning, with eis-1,4-dichloro- or -l, 4-dibromo-2-butene in the presence of an alkoxide, a hydride or an amide of an alkali metal used in excess; b) reacting the compound obtained of formula: in which R and R1 have the meaning given above and X is chlorine or bromine, with a second excess of an alkoxide, a hydride or an amide of an alkali metal; c) reacting the tricyclic ketone obtained of formula: in which R and R1 have the meaning given above with a compound of formula H2NY in which Y represents hydrogen or a hydroxy, lower alkoxy or phenyl-lower alkoxy group, and d) subjecting the imino compound obtained of formula : RO in which R, R1 and Y have the meaning given above, to a reduction of the imino group of this compound. 2 2. Method according to claim 1, characterized in that an alkali metal in an alkanol is used for the reduction of the imino group. 3 617,664 in which R1 represents a methyl or ethyl radical, characterized in that a compound of formula I is prepared by the process according to claim 1, the ether function is split, and the non-aromatic double bond is then reduced. 3. Process for the preparation of a compound of formula: NH, in which R1 represents a methyl, ethyl or lower alkenyl group, characterized in that a compound of formula: RO NH, in which R and R1 have the meaning given to claim 1, and the ether function is split. 4. Method according to claim 3, characterized in that a Lewis acid is used as the scission reagent. 5 5. Method according to claim 4, characterized in that the Lewis acid is boron tribromide. 6. Process for the preparation of a compound of formula: RO NH in which R represents a lower alkyl or phenyl-lower alkyl group and Rla represents a methyl or ethyl radical, characterized in that a compound of formula is prepared, by the process according to claim 1: Horn in which R and Rla have the meaning given above and the non-aromatic double bond is reduced. 7. Method according to claim 6, characterized in that the reduction of the non-aromatic double bond is carried out by catalytic hydrogenation. 8. Method according to claims 1 and 6, characterized in that, in the last step of the process, the imino and non-aromatic double bonds are reduced simultaneously. 9. Method according to claim 8, characterized in that the reduction of the imino and non-aromatic double bonds is carried out by catalytic hydrogenation. 10 10. Process for the preparation of a compound of formula: HO, 11. Method according to claim 10, characterized in that the reduction of the non-aromatic double bond is carried out by catalytic hydrogenation. 12. Method according to claim 1, characterized in that an acid addition salt of a compound obtained is prepared. 13. Method according to claim 1, characterized in that an acid addition salt of a compound obtained is transformed into the free amine. 14. Method according to claim 1, characterized in that a mixture of optical isomers obtained is obtained in order to prepare a diastereomeric pair or an individual enantiomer. 15. Process for the preparation of a compound of formula: RO NR R in which R2 represents hydrogen or a lower alkyl, lower alkenyl, lower alkynyl or lower phenylakyl group, and R3 represents a lower alkyl, lower alkenyl, lower alkynyl or lower phenylalkyl group, characterized in that a compound is prepared ( I) by the process according to claim 1, and then it is reacted with a compound of formula R3-Hal or else with compounds of formula R3-Hal and R2-Hal, Hai being a halogen, or else with formaldehyde in the presence of formic acid, to obtain the corresponding secondary or tertiary amine and, where appropriate, their acid addition salts. 15 20 25 30 35 40 45 50 55 60 65 16. Process for the preparation of a compound of formula: HO NR R in which R2 represents hydrogen or a lower alkyl, lower alkenyl, lower alkynyl or phenylalkyl group and R3 represents a lower alkyl, lower alkenyl, lower alkynyl or lower phenylalkyl group, characterized in that a compound (I ) by the process according to claim 1 and then the ether function is split and the compound obtained is reacted with a compound of formula R3-Hal or else with compounds of formula R3-Hal and R2-Hal, Hai being a halogen, or with formaldehyde in the presence of formic acid, to obtain the corresponding secondary or tertiary amine and, where appropriate, their acid addition salts. 17. The method of claim 15 for the preparation of a compound in which R1 represents a methyl or ethyl group, and R2 and R3 are independently chosen from lower alkyl and lower phenylalkyl radicals, R2 can also represent hydrogen. 18. The method of claim 16 for the preparation of a compound in which R1 represents a methyl or ethyl group, and R2 and R3 are independently chosen from lower alkyl and lower phenylalkyl radicals, R2 also being able to represent hydrogen.