CS196407B2 - Process for preparing derivatives of 2-phenylbicyclooctane and octene - Google Patents

Description

The invention relates to a process for the production of a novel class of 2-phenylbicyclooctane and octene derivatives which preferably act / ha of the central nervous system. '' ''

No. 2,354,931 of the same Applicant describes and claims a group of transderivatives which also have a 2-phenylbicyclooctane core and which affect the central nervous system. U.S. Pat. Nos. 3,308,160 and 3,362,787 also disclose bicyclooctans with action on the central nervous system.

The present invention relates to a process for the preparation of an amine of formula (I)

or. an acid addition salt thereof, of the formula

R ¹ is alkyl of 1 to 4 carbon atoms,

R ² is hydrogen or alkyl of 1 to 4 carbon atoms and

R ³ and R ⁴ each concept is a hydrogen atom, wherein these hydrogen atoms are in cis -196407 of, or together represent a single chemical bond, and

Ar represents a phenyl group substituted by at least one atom or a group comprising hydrogen, halogen, trifluoromethyl, nitro, dialkylamino of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or alkylenedioxy in racemic or (+) or the (-) enantiomeric form, which comprises condensing an amine of the general formula

HNRlR ^2, in which

R ¹ and R ² are as defined above, with a compound of formula VIII,

in which

R ³ , R ⁴ and Ar are as defined above and Q is a moiety selected from the group consisting of 198407

Halogen, alkylsulfonate, optionally, if any

R ³ and R ⁴ represent the hydrogen atoms in the cis position, the obtained compound of formula I formed by condensation, cleaves into its (+) or (-] enantiomeric form.

It will be apparent to those skilled in the art that the compounds of formula (I) may exist in two optical isomers, and it will be understood that the invention relates to both the (+) and (-) forms as well as their racemic mixtures.

When R ³ and R ⁴ together represent a single chemical bond, the 2-phenylbicyclo-2-octene of formula I may have the formula:

IV.

Ar (IV)

The substituted phenyl Ar group in the compounds of Formula I has the formula

in which

R ⁵ and R ⁶ individually represent the same or different substituents selected from the group consisting of hydrogen, halogen, trifluoromethyl, nitro, amino, acylamino of 1 to 5 carbon atoms, mono- or dialkylamino of 1 to 4 carbon atoms, alkyl (C 1 -C 4 or C 1 -C 4 alkoxy) or together represent C 1 -C 4 alkylenedipxy.

Preferred compounds of formula I are those having one or more of the following characteristics:

and R ¹ is C 1 to C 4 alkyl and R ² is hydrogen or methyl or ethyl;

b) R ¹ and R ² are the same or different C 1 -C 8 alkyl groups;

c) R ¹ and R ² are methyl; , ·

d) R ³ and R ⁴ are cis-hydrogen atoms; e) Ar is phenyl substituted with halogen at the 2,6-position; 2, 5; 2, 4; 2, 3; 3, 5 or 3, 4;

f) Ar is phenyl mono- or di-substituted by halogen;

g) Ar is p-chloro or p-bromophenyl;

hj Ar is 3,4-dichlorophenyl or

i) R ³ and R ⁴ are cis-hydrogen atoms and the compound of formula I is the (-j) enantiomer.

. Most preferably, the compounds of formula I have properties a), d) and f}; aj and e); c), f j and ij; c) and g); or c), h) and i).

.

To be sure, the term "alkyl of 1 to 4 carbon atoms" as used herein either explicitly or implicitly, as in the term "acylamino of 2 to 5 carbon atoms", includes any alkyl group, linear or branched, of 1 to 4 carbon atoms. 4 carbon atoms. Thus, R ¹ and / or R ² may be methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, s-butyl or Ubutyl. Similarly, the term "halogen" denotes fluorine, chlorine, bromine or iodine.

At the same time, the following compounds of the invention are preferred:

cis-3-N, N-dimethylaminomethyl-2- (p-chlorophenyl) bicyclo [2.2.1] octane; >

cis-3-N-methylaminomethyl-2- [p-chlorophenyl] bicyclo [2.2.2] octane;

cis-3-N, N-dimethylaminomethyl-2- (3,4-dichlorophenyl) bicyclo [2.2.2] octane;

cis-3-N-methylaminomethyl-2- (3,4-dichlorophenyl) bicyclo [2.2.2] octane;

cis-3-N, N-dimethylaminomethyl-2- (p-bromophenyl) bicyclo [2.2.2] octane cis-3-N-methylaminomethyl-2- (p-bromophenyl) bicyclo [2.2.2] octane;

and their (- (-) enantiomers);

3-N-methylamino-methyl-2- (3,4-dichlorophenyl) bicyclo [2.2.2] -2-octene;

3-N, N-dimethylaminomethyl-2- (3,4-dichlorophenyl) bicyclo [2.2.2] octene.

According to the invention, there is provided a process for the preparation of a compound of formula I or an acid addition salt thereof, which also comprises a reduction

i) compounds of formula V R- (CH ₂ ) n, -Z (V) wherein m is 0, 1 or 2; and

Z is - CONR ¹ R ² , - CH = NR ¹¹ OR - C (OR ¹ ) = NR ¹ ;

or 11] an olefin of formula VI,

where,

R ⁷ and R ® together represent a single bond or

R ³ and R ⁴ together represent a single bond, independently represent hydrogen atoms

B) alkylation of a compound of formula VII,

R - (CH 2) _n NHR ^2? , (VII) or

C) condensation of an amine of the formula

HNRt _R 2, a compound of formula VIII R- _(CH2) '- Q (VIII) wherein

Q is a residual group; optionally followed when.

R ³ and R ⁴ 'represent cis-hydrogen atoms,

D) cleavage of the product of formula I formed in reaction A) or Bj or C) into its (- + -) or (- enantiomeric form),

Preferred methods of preparation of the present invention include the use of an intermediate of formula (IX),

R (CH 2) _m —Z ', (IXj in which m is as defined above, ie η — 1, and wherein

Z 'represents Z or -CHO, -CN, COC1, CONH2, CH2 NC or COOR ⁹ wherein R ⁹ is alkyl of 1 to 4 carbons, which may, if preferred, be reacted in situ in the reaction medium, in which creates.

When R is a bicyclooctane core, the use of a nitrile intermediate is more preferred because cis-nitrile is thermally stable and the nitrile group is a good activating group in the Diels-Adler reaction by which this group of intermediates is prepared.

The compounds of formula (IX) are readily converted to compounds of formula (I) or to their primary amino analogs by reduction, although when R ³ and R ⁴ represent a single bond, precautions must be taken to prevent reduction of the olefinic moiety.

In the case of the nitriles and amides of formula IX, the reduction is preferably carried out using a complex hydride reducing agent depending on such factors as sodium hydride, while in the case of the isocyanates of formula IX treatment with concentrated mineral acid such as hydrochloric acid produces the desired conversion. The aldehydes and esters of formula IX can be reductively aminated to the desired compounds of formula I by reduction to the corresponding alcohols, for example, using a complex hydride reducing agent, by converting the alcohols to the corresponding alkyl or arylsulfonates (by reaction with alkyl or arylsulfonyl chloride and reacting the sulfonates with an amine of the formula HNR ¹ R ² :

Reduction animations of aldehydes of formula IX can also be performed by catalytic hydrogenation in the presence of ammonia or an amine of formula HNR ¹ R ² .

Alternatively, compounds of formula IX wherein Z 'is -CHO may be condensed directly with an amine to give the corresponding Schiff base, which may be reduced with a complex hydride, preferably sodium borohydride, to give a compound of formula I wherein R is ² is hydrogen.

Where Z ‘is - CN, - CONH 2 or CH 2 NHCO, or the above reductive amination is carried out in the presence of ammonia, the resulting product is a primary amine of the formula

R 2 - (CH 2) _n NH 2, which can then be alkylated to a compound of formula I wherein R ¹ and / or R ² is an alkyl of 1 to 4 carbons. Alkylation can be carried out in a conventional manner, for example by reductive alkylation, reaction with an alkyl halide; Similarly, monoalkylated products of formula I, i.e., compounds of formula I, wherein R ² is hydrogen, can be alkylated to form dialkylated products of formula I, wherein R ² is alkyl of 1 to 4 carbon atoms.

In the case where Z 'is CN, a compound of formula I in which R ¹ is hydrogen and R ² alkyl of 1 to 4 carbon atoms, treatment with the corresponding oxonium salt, followed by addition of the corresponding alcohol and reduction with sodium borohydride can be obtained [see J. Org. Chem. 34, 627/1969]]. This reaction can be schematically illustrated by:

--CH ^ ^ dí dí dí dí dí dí (((((· (((((((((((((((((((((((((((((((((C) _ra )

NaBH ^

R-1CtylNHR ¹

The above intermediates of formula IX, except for a compound wherein R is a bicyclooctane ring, m is 0, Z ‘is CN and Ar p-chlorophenyl, are novel and accordingly form part of the invention.

They can be obtained from the nitrile of formula X by the following sequence of reactions in which R, R ¹ , R ² and R ^a are as defined above.

(XJ

R-CH = CHCOOH ·

R <OQH <= frCOOR R-CHOR-CHgCN H-coci ^ e ^ r-conr ¹ ^

K ^-CHiCOORr-ch _from coohh

1 ^D

R-CH-HCO

R-CHgCHO? -?

F ^ R-CHiCONR ¹ R ¹ ·

R -CHCHCW CRRCH íNCO

1 °

R - (CH3) CH4 - - R - ICH, 1;

III

R ^ COOH ’H

R-tCH 2 NCO

When R ³ and R ^{4 are} C ¹ -hydrogen atoms, cis-6-phenylbicyclo [2.2.2] 2-octene-5-carbonitrile of formula X can be prepared from the corresponding aldehyde of the following formula XI

by reaction with hydroxylamine, followed by dehydration of the oxime thus prepared by a suitable dehydrating agent, for example P2O5 or cyanuric chloride.

Alternatively, and preferably, the aldehyde of formula XI is directly converted to the acid of formula RCOOH by selective hydrogenation, followed by treatment of the partially reduced aldehyde with Jones reagent (Na 2 C 2 O 2 / H 2 SO 4).

The aldehyde of formula XI can be prepared by a Diels-Alder reaction between the corresponding phenylpropargylaldehyde and 1,3-cyclohexadiene.

Said reaction and allows reduction of a compound of formula X, using for example hydrogen in the presence of a suitable catalyst such as palladium on activated carbon to form a nitrile of formula IX in which m is 0. It is understood that when R ³ and R ⁴ represent a single bond, selective hydrogenation must be used, the reaction being stopped after one mole of hydrogen has been reached.

Reaction B is carried out by hydrolysis, as is well known, and the resulting carboxylic acid can then be converted to the corresponding acid chloride - reaction D - in a known manner, for example by reaction with thionyl chloride. The chloride can then be converted by Arndt-Eistertoy synthesis - reaction F - to substituted acetic acid, and by repeating reactions D and F, similarly substituted propionic acid and butyric acid can be obtained.

The above substituted propionic acid can also be prepared from the aldehyde R-CHO by reactions I and J, reaction I being a well-known Knoevenagel reaction to produce a 3-substituted acrylic acid and reaction J allows acrylic acid reduction using, for example, hydrogen on a palladium catalyst for production of the desired propionic acid.

The reaction can convert the aforementioned carboxylic acid, substituted acetic acid or substituted propionic acid into the corresponding nitriles of formula IX in which m is 0, 1 or 2. Reaction C can be carried out by treating the acid with ammonia at elevated temperature in the presence of alumina. The acid chlorides formed by said reaction D are readily converted - reaction E - to the desired amides of formula IX by reaction with the corresponding amine of formula NHR ¹ R ² .

Further, by reducing the substituted acetyl chlorides and propionyl chlorides previously formed - the reactions - the desired aldehydes of formula IX in which m is 1 or 2 can be obtained. The well known Rosenmund reaction provides one means for completing this reduction, the above-substituted acetic acid. propionic and butyric can also be converted by reaction H to the desired isocyanates of the formula IX in which m is 0, 1 or 2. This conversion can be carried out by forming the appropriate azide of the acid, either by treating the corresponding. sodium azide, or by forming an appropriate acid hydrazide and treating it with nitrous acid, and then heating the acid azide in a benzene or chloroform solution. \

Reaction K allows for the conventional esterification of the corresponding acid, for example by reaction with an alcohol R ⁹ -OH. Esters of formula IX in which

wherein reaction A is as described above, wherein the compound of formula IX, wherein R is a bicyclooctane ring, is obtained by a Diels-Alder reaction between the corresponding cinnamic acid nitrile and 1,3-cyclohexadiene followed by hydrolysis followed by esterification. The resulting ester can then be hydrolyzed - reaction L - to give the corresponding acid. Reaction M can be carried out by the well known Rosenmund reduction. ,

As mentioned above, reaction A allows reduction, for example by catalytic hydrogenation, and it will be apparent to those skilled in the art that when Ar is substituted with a nitro group, this group can be partially or completely reduced to the corresponding amino substituted product.

Thus, if a nitrosubstituted product is desired, the corresponding intermediate. of formula IX is preferably obtained by nitration after reaction A and subsequent conversion of the nitrated intermediate. the desired compound of formula I is carried out under conditions which reduce the nitro substituent. Compounds of formula I may also be prepared by reduction of an olefin of formula VI, as previously mentioned. This reduction can be carried out using hydrogen on a catalyst such as eighth metal, for example platinum or palladium. The catalyst may be supported on an inert support such as activated carbon. To carry out the reaction, the unsaturated compound of formula VI can be dissolved in a suitable inert solvent, for example ethanol or ethyl acetate. To produce a compound of formula I in which R ³ and R ⁴ represent a single bond, selective hydrogenation of the R ⁷ / R ⁸ olefinic group must be performed.

Compounds of formula VI are novel. They can be prepared from compounds of formula XIII,

in which

R ⁷ and R ® are as in formula VI and wherein

Z * is -CHO, CO 2 H, CO 2 R ⁹ or CN, by any of the methods described above for converting the same T groups in the compound of formula IX to-NR R R ² , provided that these modifications do not destroy the unsaturated nature of the bicyclooctene moiety.

Compounds of formula XIII in which R ³ and R ⁴ together represent a single bond, R ⁷ and R ® hydrogen atoms and Z * aldehyde group can be prepared by:

A Diel-Alderovob reaction between the appropriate trans-innamaldehyde and 1,3-cyclohexadiene, followed by catalytic reduction, copper bromide bromination and subsequent dehydrobromination, preferably with a mixture of lithium chloride with lithium carbonate; or

2. Diels-Alder reaction between the corresponding phenylpropargylaldehyde and 1,3-cyclohexadiene, followed by catalytic reduction.

Compounds of formula XIII, where R ⁷ and R ® together represent a single bond and Z * is CHO, may be prepared by a Diels-Alder reaction between 1,3-cyclohexadiene and an aldehyde of formula

ArR ⁴ C = CR ³ CHO.

Analogs, acid, acid chloride, ester and nitrile can likewise be prepared using appropriate modifications of the above synthetic procedures.

The preparation of compounds of formula XIII in which R ⁷ and R ⁸ represent a single bond, R ³ and R ⁴ cis-hydrogen atoms and Z 'is a nitrile has been previously described. Such compounds can be converted to the corresponding acid, ester derivatives, etc. by the methods mentioned. formerly for the compounds of formula X, however, reduction step A should be omitted.

Another method for preparing amines of formula I allows condensation of a compound of formula VIII, R - (CH 2) _{n -} Q (VIII) wherein

Q is a radical comprising a reactive atom, such as a halogen atom, for example iodine, or a reactive group, such as a sulfonate, for example mesyl or tosyl, with an amine of the formula

NHRiR ² , where - '·

R ¹ , R ¹ and R ² are as defined above. ,

This type of reaction is well known and one of ordinary skill in the art will readily determine the nature of the reaction conditions required to conduct the reaction and the appropriate Q radicals. However, by the way, it may be noted that, as the reaction proceeds to eliminate HQ, the presence. a proton acceptor, such as a base, is suitable. If desired, the reaction may be carried out in the presence of a suitable solvent such as methylene chloride or dimethylsulfoxide.

Compounds of formula VIII may be derived from the corresponding alcohols of formula XIV. '.

i *

R (GH2) OH (XIV)

For example, to obtain a compound of formula VIII wherein Q is chlorine, the above alcohol can be reacted with phosphorus pentachloride or oxychloride, and to obtain. such a compound in which Q is tosyl or mesyl, the alcohol can be reacted with p-toluenesulfochloride or methylsulfonyl chloride.

Alcohols of formula XIV may be derived from aldehydes of formula:

R - (CH 2) _m CHO by reduction using an alkali metal borohydride such as sodium borohydride or lithium aluminum hydride.

Intermediates of formula VIII and XIV are novel compounds and are a further aspect of the invention.

It will also be apparent to those skilled in the art that the resulting compound of formula I in which Ar is substituted with an amino group can be converted to other compounds of formula I in a conventional manner. Thus, the amino-substituted compound may be acylated to form the desired product of formula I wherein Ar is substituted with a C 2 to C 8 acylamino group or mono- or di-distal to form the desired compound in which Ar is substituted with a mono- or di-alkylamino group having 1 to 4 carbon atoms. Further, the amino-substituted product can be diazotized and the resulting diazonium salt converted to various other products, for example, by decomposition in an alcohol to give the corresponding C 1 -C 4 alkoxy substituted compound or by reaction with copper (I) halide to give the corresponding halogen substituted compound of Formula I.

The compounds of formula I formed by the foregoing processes can be isolated as such or in the form of an acid addition salt.

Acid addition salts are preferred for pharmaceutical use, namely non-toxic acid addition salts with suitable acids such as anorganic acids such as hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acids, or with organic acids such as organic carboxylic acids, for example, glycollic, maleic, hyd196407 ¹³ roxymaléinová, malic, tartaric, citric, salicylic, o-acetoxyb.enzoová, nicotinic or isonicotinic acid, or organic sulfonic acids such as methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic acid, p-toluenesulfonic or 2-naphthalenesulfonic.

. Apart from pharmaceutically acceptable acid addition salts, other salts are also included within the scope of acid addition salts, such as picric or oxalic acid salts; They may serve as intermediates in the purification of compounds or in the preparation of other, for example, pharmaceutically acceptable acid addition salts, or are useful in identifying, characterizing or purifying a base.

The resulting acid addition salt can be converted to the free compound by known methods, for example by treatment with a base such as. a metal hydroxide or alcoholate, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide; a metal carbonate such as an alkali metal or alkaline earth metal carbonate or bicarbonate; with ammonia; or with a hydroxyl ion exchange or other suitable agent.

The resulting acid addition salt can also be converted to another addition salt by known methods; for example, an inorganic acid salt can be treated with a metal salt, for example sodium. barium or silver acid salts in a suitable solvent in which the resulting inorganic salt is insoluble, and thus removed from the reaction medium. The acid addition salt can also be converted to another acid addition salt by treatment with ion exchangers.

As mentioned previously, when R ³ and R ⁴ represent cis-hydrogen atoms, the compound of formula I may exist in two enantiomeric forms. Although the racemate has antidepressant activity per se, under certain circumstances it may be desirable to resolve the racemate into the dextrorotatory (-J-) and the levorotatory (-j form).

The cleavage can be carried out by any method conventionally used in the resolution of active bases, such as reaction with optically active acids of known stereochemistry, followed by fractional crystallization of the formed salts.

Suitable optically active acids which may be considered are (+) or (-) tartaric, malic, mandelic or sulfocapric acid, the latter being preferred.

It has been found that the (- (-) enantiomers of the compounds of formula I) have particularly specific CNS activity.

The compounds of formula I and their pharmaceutically acceptable acid addition salts have antidepressant activity and are therefore useful for treating various depressive conditions in mammals. Their utility has been demonstrated in well known test procedures such as reserpine hypothermia antagonism in mice and inhibition of noradranalin (NA) and 5-hydroxytriptamine (5HT) rebound in mouse brain synaptosomes. They have low toxicity.

As noted above, the active compounds of the invention form acid addition splices and where these salts are pharmaceutically acceptable, they are equally suitable for processing herein. The active compounds and their pharmaceutically acceptable acid addition salts of the invention are effective over a wide dosage range, the actual dosage administered being dependent on such factors as the compound employed, the condition being treated and the type and size of mammal to be treated. The desired daily dose will normally fall within the range of 0.1 to 20 mg / kg, for example in the treatment of adult humans, with a single dose of 0.1 to 5 mg / kg being used, while in the treatment of test animals such as mice and rats. , single doses of from 1 to 50 mg / kg may be used.

. The active compounds and salts of the invention will normally be administered orally or by injection, and for this purpose the compounds will usually be employed in the form of a pharmaceutical composition. These mixtures are prepared in the fares; They may contain at least one active compound or salt of the invention together with a pharmaceutically acceptable carrier.

In the manufacture of the compositions of the invention, the active ingredient is usually admixed with the carrier or diluted or enclosed within a carrier, which may be in the form of a capsule, paper or other carrier. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that serves as a vehicle, excipient, or medium for the active ingredient. Examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, syrup, methylcellulose, methyl- and propylhydroxybenzoate, talc, magnesium stearate or mineral oil. The compositions may be formulated, as is known, to ensure rapid, supportive, or delayed action of the active ingredient after administration to the patient.

Depending on the route of administration, the foregoing compositions may be formulated as tablets, capsules or suspensions for oral use and injectable solutions for parenteral use. Typically, the compositions are formulated in a unit dosage form, each dosage containing from 1 to 500 mg, usually 5 to 250 mg, of the active ingredient.

It will be appreciated that the preferred features following the initial description of the compounds of Formula I may be applied with appropriate changes to all other aspects of the invention.

The invention will now be described with reference to the following Examples.

He did

3-N, N-Dimethylaminomethyl-2-phenylbicyclo [2.2.2] -2-octene hydrochloride

IS '(&'): · .. ··. ·

3-Formyl-2-phenylbicyclo [2.2.2] -2,5-octadiene

1,3-Cyclohexadiene (70% solution, 10 mL, 0.09 mol) and afenylpropargylaldehyde (4 g, 0.03 mol) were refluxed in the presence of several hydroquinone crystals for 5 days. The solution was evaporated and the residue distilled. Yield 3.8 g (61 percent), mp 110-120 ° C at 0.1 mmHg. NMR analysis showed that the mixture contained 75 percent of the desired product.

(b). ·· · '. '.

3-Formyl-2-phenylbicyclo [2.2.2] -2-octene

3-Formyl-2-phenylbicyclo [2.2.3.1] -2,5-octadiene (3.7 g, 0.018 mol), 5% palladium on charcoal (0.3 g) and ethyl acetate (100 mL) were The catalyst was filtered off and the filtrate was evaporated, the residue was then distilled twice, yield 1.9 g (51%), mp 160 ° C at 0.2 mm Hg.

(E)

3-Formyl-2-phenylbicyclo [2.2.2] -2-octene (alternative method) tans-3-Farmyl-2-phenylbicyclo [2.2.2: octane (10.7 g, 0, 05 mol) in chloroform (50 ml) was added to copper (I) bromide (22.3 g; 0.1 mol) in ethyl acetate (50 ml). The mixture was refluxed for 4 hours, left overnight at room temperature, treated with charcoal and evaporated to give 3-bromo-3-formyl-2-phenyl-bicyclo [2.2.2] octane as brown oil (mp 65-66 ° C after crystallization from ethanol). The oil was dissolved in dimethylformamide (50 µl) and lithium bromide (5 g, ~ 0.0057 mol) and lithium carbonate (5 g, 0.078 mol) were added and the mixture was boiled for 2 hours. After pouring into water (600 mL) and extracting with ether, the ether was washed, dried (MgSO 4) and evaporated to give an oil which was distilled. Yield 8.8 g (76%), b. T 160'C at 0.2 mm Hg.

(d)

3-Hydroxymethyl-2-phenylbicyclo [2.2.2] -2-octene

To lithium aluminum hydride (1 g, 0.03 mol) in ether (50 mL) was added 3-formyl-2-phenylbicyclo [2.2.2] octane (4.2 g, 0.02 mol) ether (40 mL) dropwise at 0 ° C. After 1 hour, 5N sodium hydroxide (1 mL) was carefully added followed by water (5 mL). After filtration, the filtrate was evaporated to give an oil which was used directly in (e) below.

3-N, N-Dimethylaminomethyl-2-phenylbicyclo [2.2.2] -2-octenohydride chloride;

To 3-Hydromethyl-2-phenylbicyclo [2.2.2.1] -2-octene (1.4 g, 0.008 mol) dichloromethane (20 mL) and trlethylamine (5 mL) at 0 ° C was added methanesulfonyl chloride (2, 2, 2, 3, 4 mL, 20% excess) dropwise. After 1 day at 0¾, the mixture was poured on ice and extracted with dichloromethane. The dichloromethane was dried (MgSO4) and evaporated to give an oil (1.7 g). The oil was dissolved in dichloromethane (20 mL) and added to dimethylamine (15 mL of a 30% solution in ethanol) at 0 ° C. After stirring at room temperature for 3 days, the solution was evaporated and the residue dissolved in 5N HCl and extracted with ether. The ether was dried (MgSO 4) and evaporated to give an oil (0.5 g) which, when dissolved in ethanolic hydrogen chloride solution, formed white needles. Yield 0.48 g (26%), mp 236-237 ° C.

Example 2

Cis-2- (3,4-dichlorophenyl) -3-N, N, -dimethylaminomethylbicyclo [2.2.2] octane hydrochloride

This compound was prepared from cis-2- (3,4-dichlorophenyl) -3-hydroxymethylbicyclo [2.2.2] octane as in Example 1 (e). Cis-2- (3,4-dichlorophenyl) -3- N, N-dimethylaminomethylbicyclo [2.2.2] octane was obtained as an oil which upon dissolution in ethanolic hydrogen chloride solution and addition of ether formed the title compound, mp 223-225 degrees Celsius.

EXAMPLE 3 (+) and (-) cis-2- (3,4-Dichlorophenyl) -3-N, N-dimethylaminomethylbicyclo [2.2.2] octane hydrochloride

The amine hydride chloride product was dissolved in hot water containing enough ethanol to dissolve. Then excess potassium carbonate solution was added and the mixture was stirred. The free base thus obtained was then extracted with ether, the ether extracts dried over magnesium sulfate, filtered and evaporated to give an oil which crystallized after standing for several days.

The crystalline free base was then dissolved in cold ethyl acetate (2.63 g, in 25 mL) containing ethanol (2.5 mL). D - (-) - Sulfocaproic acid (1.95 g), dissolved in hot ethyl acetate (25 mL) was added to this solution. The combined solution was slowly stirred until white crystals of the acid amine salt crystallized. The reaction mixture was then allowed to stand for 24 hours and the salt was recovered by filtration. This salt is recrystallized again

6 40 7 from ethyl acetate and ethanol until a constant melting point and specific rotation was obtained. - _? [Α] 23 _d = + 81 ° (C = 0.5%, ethanol)

mp, 219 ° C

The pure sulfocapric amine salt was then dissolved in hot water and potassium carbonate was added to liberate the free base, which was extracted with ether. The combined ether extracts were dried, filtered and evaporated to an oil. This oil was dissolved in ethanol. HCl was then added to the solution and enough ether to allow crystallization of the hydrochloride salt overnight. White HCl The salt that formed was (+) - cis -2- (3,4-dichlorophenyl) -3-N, N-dimethylaminomethylbicyclo [2.2.2] octane hydrochloride [α] D ²² = +99 ° (C = 0.4%, ethanol]

1.1. Mp 224-226 ° C.

Similarly, using iododification of the above cleavage method, -) - cis-2- (3,4-dichlorophenyl) -3-N, N-dimethylaminomethylbicyclo [2.2.2] octane hydrochloride [α] _D ²² = ggo (C) was obtained. = Q, 4%, ethanol).

Examples 4 to 2.1

The following compounds of the invention were prepared using procedures similar to those described in Example i, paragraph (e):

cis-3-N-methylaminomethyl-2- (p-tert-butylphenyl) bicyclo [2.2.2] octane hydrochloride (mp 273-276 ° C), cis-3-N-methylaminomethyl-2- [2,4 -dichlorophenyl) bicyclo [2.2.2] octane hydrochloride (mp 265-267 ° C), cis-3-N, N-dimethylaminomethyl-2- (p-bromophenyl) bicyclo [2.2.2] octane hydrochloride ( mp 238 ^and C), cis-3-N-methylaminomethyl-2- (p-bromophenyl) bicyclo [2.2.2] octane hydrochloride (mp 24PC);

cis-3-N-methylaminomethyl-2- (4-chloro-3-trifluoromethylphenyl) bicyclo [2.2.2] octane hydrochloride (mp 223 C, ^D), IA cis-3-N, N-dimethylaminomethyl-2- (3,4-methylenedloxyphenyl) bicyclo [2.2.2] octane maleate (mp 124-125 ° C),

3-N-methylaminomethyl-2- (4-nitrophenyl) bicyclo [2.2.2] -2-octene hydrochloride (m.p. 246-247 ° C),

3-N-ethylaminomethyl-2- (4-chlorophenyl) bicyclo [2.2.2] -2-octenhydrochloride (mp 251-253 ° C),

3-N-methylaminomethyl-2- (4-chlorophenyl) bicyclo [2.2.2] -2-octene hydrochloride (mp 195 ° C), cis-3-N, N-dimethylaminomethyl-2- (o-chlorophenyl) bicyclo [2.2.2] 2] octane hydrochloride (mp 215-217 ° C), cis-3-N, N-dimethylaminomethyl-2- (m-chlorophenyl) bicyclo [2.2.2] octane hydrochloride (mp 260-207 ^and C), cis -3-N, N-Dimethylaminomethyl-2-phenylbicyclo [2.2.2] octane hydrochloride (mp 220-223 ° C), cis-3-N, N-dimethylaminomethyl-2- (fluorophenyl) bicyclo [2, 2,2-ioctane hydrochloride (mp 232-234 ° C), cis-2- (pfluorophenyl) -3-N-methylaminomethylbicyclo [2.2.2] octane hydrochloride (mp 236-238 ° C), cis-2- (3, 6-chloro) 4-dichlorophenyl) -3-N-methylaminomethylbicyclo [2.2.2] octane hydrochloride (mp 247-248 ° C), cis-3-N-methylaminomethyl-2-phenylbicyclo [2.2.2] octane hydrochloride (213-215 ° C) C),

3-N-methylaminomethyl-2- (3,4-dichlorophenyl) bicyclo [2.2.2] -2-octene hydrochloride (m.p. 247-249 ° C),

3-N, N-dimethylaminomethyl-2- (3,4-dichlorophenyl) bicyclo [2.2.2] -2-octene hydrochloride (m.p. 204-207 ° C).

19.940 7

Claims (1)

Subject OF THE INVENTION A process for the preparation of 2-phenylbicyclooctane and octene derivatives of the general formula I. JI) or an acid addition salt thereof, of the formula R ¹ is alkyl of 1 to 4 carbon atoms, R ^z is hydrogen or alkyl of 1 to 4 carbon atoms and R ³ and R ⁴ each represent a hydrogen atom, these being hydrogen. the hydrogen atoms are in the cis position or together represent a single chemical bond, and * Ar represents a phenyl group substituted by at least one atom or a group selected from hydrogen, halogen, trifluoromethyl, nitro, dialkylamino of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or alkylenedioxy in racemic or ( + -) or (-) enantiomeric form; The process is characterized in that the amine of the general formula is condensed HNR ¹ R ² wherein R ¹ and R ² are as defined above, with a compound of formula VIIa (VIII), wherein R ³ , R ⁴ and Ar are as defined above, and Q is a residue selected from the group consisting of halogen, alkylsulfonate, and optionally, when R ³ and R ⁴ represent the hydrogen atoms in the cis position, the obtained compound of formula I formed by condensation, cleaves into its (+) or (-) enantiomeric form.