SI8510063A8 - Process for obtaining (1-arylcyclobutyl)alkylamines - Google Patents

Description

PROCEDURE FOR OBTAINING. (1-arylcyclobutyl) ALKYLAMINE *

FIELD OF THE INVENTION

The invention relates to the synthesis of novel alicyclic amine derivatives.

Technical problem

A technical problem that is solved in the present invention is the expansion of an existing range of antidepressant drugs. The technical problem has been solved in such a way that a process for the preparation of new (1-arylcyclobutyl) alkylamines which has been shown to have excellent antidepressant properties is provided

The state of the art

1- (Arylcyclobutyl) alkylamines obtained by the process of the present invention are not known in the literature. However, a careful look at the Derwent Central Patents Index from 1963 to the present and Chemical Abstracts found four references describing arylcyclobutylalkylamines. All of these compounds differ in. the quality of the substitution of the compounds made by the method of the present invention and, in addition, none of these known compounds has been used as a medicament with antidepressant properties. According to Torne, finding for. sought protection is an analogous process for the preparation of novel (1-arylcyclobutyl) alkylamines with antidepressant properties.

The four references mentioned are:

British Patent 973887 to Farbwerke Hoechst Aktiengesellschaft;

British Patent 1530172 to Rohm. & Haas Company (see especially pp. 2, lines 21 and 22);

Chemical Abs £ ractsjB7 232365 ind. and «, Chem. Section B 1976 14B 766;

Chemical Abstracts 85 32678 Arm Khim Zh. 1976 29 (2) 194.

Description of a solution to a technical problem with performance examples *

The present invention provides a process for the preparation of compounds of formula I:

CHR / cHR _r ) _n NH _with I

in which n = 0 or 1;

in which, when n = 0, the alkyl group is a straight or branched chain containing 1 to 4 carbon atoms, a cycloalkyl group containing 3 carbon atoms or a phenyl group, when n = 1, ^R ! is H;

wherein R, vi Rg, which may be the same or different, H, halo, trifluoromethyl, methyl group, methoxy group, phenyl, or R4 and Rg, together with the carbon atoms to which they are attached, form a second benzene ring;

and wherein R1 is an alkyl group containing 1 or 2 carbon atoms;

and pharmaceutically acceptable salts thereof.

The compounds of formula I described above can be used as intermediates which are converted into compounds of formula II or their pharmaceutically acceptable salts

in which R8 and R4, which may be the same or different, are an alkyl group of straight chili branched: a series of hexa containing 1 to 4 carbon atoms, an alkenyl group having 3 to 6 carbon atoms, an alkynyl group having 3 to 6 carbon atoms, or R ^ and R ^ together with the nitrogen atom to which they are attached form a pyrrolidine or piperidine ring. The compounds of formula II are also useful in the treatment of depression.

*

In the formulas in this application, the symbol:

represents a 1,1-disubstituted cyclobutane group of the formula:

I - ^C -PH, "2? The compounds of formula I may be prepared exist as a salt with a pharmaceutically acceptable salt of acid. Examples of such salts include hydrochloride, maleate, acetate, citrate, fumarate, tartarate, succinate, and salts with acidic amino acids such as aspartic and glutamic acid.

Compounds of formula I containing one or more asymmetric carbon atoms can be appreciated in various optically active forms. When is. n = 0 compounds of formula I contain a chiral center. Such compounds exist in two enantiomeric forms and the present invention includes both enantiomeric forms and mixtures thereof.

When n = 1, the compounds of formula I contain two chiral centers and the compounds exist in four diastereoisomeric forms. The present invention includes each of these diastereoisomeric forms and mixtures thereof.

The present invention also includes pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I together with a pharmaceutically acceptable diluent or carrier.

During therapeutic purification, active compounds aa knife · administer orally, rectally, parenterally 111 topically, preferably orally. Thus, the therapeutic compositions of the present invention may take the form of such known pharmaceutical preparations for oral, rectal, parenteral or topical administration. * Pharmaceutically acceptable carriers suitable for use in such preparations are well known in the pharmaceutical art. The compositions of the invention may contain Q.1-90k wt. of the active compound. The preparations of the invention are generally made in Jedlfil dosage form.

Oral administration preparations are the preferred preparations of the invention and these known pharmaceutical forms for such administration, for example, tablets, capsules, syrups, and injected or oily suspensions. The ingredients used in the formulation of these compounds are ingredients known in the art of ferro-pharmaceutical science. The tablets can be made by mixing the active compound with some such inert diluent as calcium-foefet in the presence of saliva agents, for example, corn acrobat, and lubricating agents, for example, magnesium stearate, and by tableting a known method. The tablets may be formulated in a manner known to the person skilled in the art so as to achieve a slight release of the Compounds from

- 5 of the present invention. Such tablets, if necessary, may be provided with internal coatings by known methods, for example, by the use of cellulose acetate phthalate. Similarly, capsules, for example, hard 1 soft gelatin capsules, containing * the active compound with or without douche strains, can be made t

by conventional methods and, where appropriate, may be provided with internal coatings in a known manner. Tablets and capsules may conventionally contain 1 to 500 mg of active compound ·

Other oral administration preparations include, for example, aqueous suspensions retained by the active compound in an aqueous medium in the presence of such a non-toxic eluent, such as sodium carboxymethylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example, walnut oil.

Px's poronelax apparatus suitable for reactive administration are those known pharmaceutical forms for such administration, for example, cocoa butter or polyethylene glycol-based cocoa suppositories.

The compositions of the invention which are useful for parenteral administration are known pharmaceutical forms for such administration, for example, sterile suspensions in aqueous and oily media or sterile solutions in a suitable solvent.

Topical Devon C preparations may disclose a matrix in which the pharmacologically active compounds of the present invention are discharged liquid compounds of WBO in contact with the skin for the purpose of transdermally administering the Compound. Alternatively, as active compounds, the types of cream or ointment may be dispersed in a pharmaceutically acceptable base.

In some formulations, it may be advantageous to use only _____., -. 6 ...-....... ·· * ·! -Ne of the eadSnjtg of the invention, about the image of a very small size, for example, obtained by grinding fluidnora enargljom.

In the compositions of the present invention, the active compound may be optionally combined with other compatible pharmacologically active ingredients.

Pharmaceutical preparations kq) and containing a therapeutically effective amount of the compounds of formula I can be used to treat depression in slaughtered animals including human whips. In such treatment, the amount of the compound of formula I that εε gives ns den is in the range of 1 to 1000 mg, preferably S to S00 mg.

The compounds of formula I are made by reducing the compounds of formula V

in which: ~ ......................... z. .

a) Z is a group of the formula CR ^ = NY where Y is a group containing a metal derived from an organometallic reagent such that compounds of formula I are obtained in which n = 0 and R ₂ , R _g and R 4 are H; i

b) Z is a group of the formula -CHR ^ CR ^ = NY where Y is a group containing a metal derived from an organometallic reagent such that compounds of formula I are obtained wherein n = 1 and R _g , R ₄ and R _g are H .

The porous reducing agents for the above reductions include sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, or boron-dimethylsulfide complex.

The compounds of formula II can be made from compounds of formula I by methods well known in the art for the conversion of primary to secondary or tertiary amines or for the conversion of secondary to tertiary amines. The following are exemplified by the following methods: a) alkylation of primary Emines of Formula 1 to obtain a secondary fortnulell amine, for example, by a process involving the • phase of protecting the primary amine with such a protecting group as phyto trifluoroethyl, by alkylation of 3β alkyl halide. and separation of the protecting group, for example, by hydrolysis »

b) alkylation of the primary amines of formula I, for example, with alkylhaloganyrium to give tertiary amines of formula I in which * · ^ 4 are the same »by alkylation of the Bekundaiviib amine of formula I, for example, ea alkyl halide to give tertiary amines of formula Ii in which fU and may be distinguished "by) the reaction of the primary amino formulas I ee of the narriuroborohydride and acetic acid to give the secondary amines of formula II in which ethyl 1 R ^ is H"

e) by reacting the primary amines of formula 1 aa with formaldehyde and formic acid such that oe is obtained by the tertiary amines of formula II in which ou is both Rg and R ^ methyl »

f) by reaction of secondary amines of formula I in which R 1 is H ea with formaldehyde and formic acid to give tertiary amines of formula II in which R 1 is methyl »

g) the background and purity of the pyramidal amines of formula I, for example, reacted with methylformiotot, and the reduction of! »yielding formamides, for example, with lithium-allutr.inium-hydride, are aocundamines of the amines of formula II in which R ^ disturbed and R ^ is H /

h) foivailing the secondary amines of formula I, not by example, by reaction with methylfomioate, and reduction of the formamides obtained, for example, by lithium aluminum hydride so that oa is obtained by the tally oral formula II in which R _{4 is} methyl.

I) eoylation of primary amines fcrrruls I, for example, by reaction of aa acyl chloride of the formula R ^ CCCl or ea anhydride of the formula (R ^ CO ^ O where j ' alkyl, alkenyl or alkynyl groups and reduction of the resulting amides, for example, with lithium aluminum hydride so that ae is given by the secondary amines of formula II in which R 1 is H

J) laurels of the secondary amines of formula I in which Jb R ^ K, for example, by reaction with an acyl chloride of the formula R ^ CGCl or ββ anhydride of foraule (R ^ COJ ^ G where R ^ _{2 is an} alkyl, alkenyl or alkynyl group by reduction of the resulting amides for example, lithium-aluminum-hydride tertiary amines in which R ^ k) by reaction of the primary amines of formula I and ea with an aldehyde of formula R _{13 are} CH0, where R ^ ₃ may be an alkyl group, an alkenyl group, or an alkyl group; or with the cata fox'mule R ^ COR ^,. wherein R ^ and R ^ may be the same or different, eu alkyl group, alkenyl group, alkynyl group, or R ^ and R ^ 5 together ea the carbon ator-n to which they are attached may prune the alicyclic ring and produce the imines or enomines obtained. on

nieu alkanyl or alkynyl, by cellellitic hydrogenation such that ee is obtained by the secondary amines of formula Uu in which R1 is CtL, -, is -CH-> ll5

1) by reaction of the primary amines of formula I aa non-geminally disuplethyl-9 Λ. - - --- - Z;

β by one alkene which retains 2 or S «glacial atoms between. {: ··. eupstituent-bearing carbon ethos which may be an "exemplary" preferred bromo, fc-toluenesulfonylacetic acid thus obtain the compound of formula II. in which Rj and R ^ together with the nitrogen to which the eu are attached form a heterocyclic ring containing no heteroatoms ---- except the nitrogen atom »-

Compounds of formula V in which Z is CR ^ = NY can be made by reacting an organometallic reagent with a cyano compound of formula VI:

Suitable organometallic reagents include Grignard reagents of the formula R ^ MgX where X is Cl, Br or J (Y = MgX).

Compounds of formula V in which Z is CHR ^ .CR ^ = NY can be made by reacting an organometallic reagent with a cyano compound of formula VII:

Suitable organometallic reagents include Grignard reagents of the formula R? MgX where X is Cl, Br or J (Y = MgX).

Cyano compounds of formula VI can be made by reacting cyano compounds of formula VIII. :

VIII with 1,3-disubstituted uis3P.iin propane, for example, 1,3-dibromopropane and such a base as sodium hydride.

Cyano compounds of formula VII in which H is can be made from cyano compounds of formula VI, for example, by the following series of reactions: *

a) hydrolysis of the cyano group to form a carboxylic acid;

b) reducing the carboxylic acid, for example, with lithium aluminum hydride or a borane-dimethylsulfide complex to form the corresponding alcohol;

c) replacing the hydroxy group of the alcohol with the leaving group, for example, with the p-toluenesulfonyloxy group and

d) by replacing the outgoing group with a cyano group.

The therapeutic activity of the compounds of formula I as shown demonstrates the ability of compounds that reverse the hypothermic effects of reserpine as follows. Male mice with Charles River CD1 strain weighing between 18 and 30 g. they are separated into groups of five and given food and water at will. After five hours, the body temperature of each mouse was measured orally and the mice were injected intraperitoneally with reserpine (5 mg / kg) in solution in deionized water containing ascorbic acid (50 mg / ml). The amount of fluid injected was 10 mg / kg body weight. Nine hours after the start of the test, the food is withdrawn but water is still available at will. 24 hours after the start of the test, mice were taken and mice were given a test compound suspended in 0.25% hydroxyethylcellulose solution (marketed under the trade name Cellosize QP 15000 by Union Carbide) in deionized water at a dose rate of 10 ml / kg body weight. weight.

Three hours later, the temperatures of all mice were taken again. The percentage rotation of reserpine-induced weight loss is then calculated by the formula:

(Temperature after 27 hours - Temperature after 24 hours) X 100 '(Temperature after 5 hours - Temperature after 24 hours)

The average value for each group of 5 mice was taken at several doses of yes _; add -do - values_for an average dose that causes 50% reversal (ED50). All compounds that are the final product

Examples given to Pasni have been given. and in ED50 values 30 mg / kg or less. It will be apparent to those skilled in the art that this test is indicative of compounds having antidepressant activity in humans.

Example 1

A solution of 4-chlorobenzyl cyanide (10 g) and 1,3-dibromopropane (7.5 ml) in dry dimethyl sulfoxide (12 ml) was added dropwise under a nitrogen mixture of sodium hydride (3.6 g) dispersed in mineral oil (3.6 g) and dry dimethyl sulfoxide (70 ml) at a temperature between 30 ° and 35 ° C. The mixture was stirred at room temperature for two hours and then propan-2-ol (10 ml) and water (150 ml) were added dropwise. The mixture is filtered through diatomaceous earth, which is sold under the registered trade name CELITE and the solid residue is washed with ether. The filtrate was extracted with ether and the ether phases were combined, washed with water, dried and evaporated. 1- (4-Chlorophenyl) -1-cyclobutanecarbonitrile (mp 116-120 ° at 0.6 mm Hg) is isolated by distillation. This procedure is a modification of the one described in Butler and Pollatz (J. Org.

Chem., Vol. 36, No. 1 9, 1971, p. 1308).

A solution of bromobenzene (15.7 g) in ether (50 ml) was added dropwise with cooling to magnesium scions (2.4 g) under a nitrogen atmosphere to form a solution of phenylmagnesium bromide. A solution of 1- (4-chloro phenyl) -1-cyclobutanecarbonitrile (19.1 g) made as described above in ether (50 ml) was added and the ether was replaced with dry toluene (130 ml). The reaction mixture was heated in a steam bath for one hour. A sample (20 ml) of the resulting solution was added to a solution of sodium borohydride (1 g) in diethylene glycodimethyl ether (60 ml) and the mixture stirred for one and a half hours. Water (60 ml) was added gently and the aqueous layer was extracted with toluene. The toluene extracts were washed with water, dried and evaporated to give a residue which was dissolved in methanol (50 ml). 6N hydrochloric acid (5 ml) was added and the solution filtered and evaporated. Drying with dry acetone gives alpha- [1- (4-chlorophenyl) cyclobutyl / benzylamine chloride hydrate (mp 277-279 ° C) (Formula I n = 0; R ^ = Ph; R2 = H; R ^, R ^ = H ; R ^ =

4-C1; R ₆ = H).

Example 2

A solution of isobutylmagnesium bromide was made by adding under isobutylbromide nitrogen (99 g) in ether (150 ml) to a mixed mixture of magnesium chips (18 g) and ether over a period of 1.75 hours. The mixture was refluxed for 30 minutes. The ether was replaced with toluene (300 ml) and the solution of 1- (4-chlorophenyl) -1-cyclobutanecarbonitrile (97.2 g) in toluene (60 ml) was added to a solution of isobutylmagnesium bromide prepared as described above over a period of 30 minutes. The reaction mixture was heated to about 90 ° C for 19 h and then cooled.

It was added dropwise with suspensions of sodium borohydride (30 g) in ethanol (750 ml) over a period of 1.75 hours. The reaction mixture was maintained at 70 ° C for two hours and then the ethanol (580 ml) was separated by evaporation. Water (70 ml) was added and 16 hours later concentrated hydrochloric acid (200 ml) was added dropwise. The toluene phase of the reaction mixture was washed, dried and the solvent was separated to leave a residue miscible with a mixture of ether and petroleum ether (i.e. 40-60 ° C) and 16N aqueous sodium hydroxide solution. The organic layer was washed, dried and evaporated to leave 1- (1- (4-chlorophenyl) cyc lobutyl / -3-methylbutylamine (i.e. 124-128 ° C / 0.2 mm Hg) as a brown oil (Formula I n = 0; R "= isobutyl; R", R_ and R. = H; R _r = 4-Cl and R _c = H)

2 j 4 o o

The primary amine (102.7 g) and 98% formic acid (310 ml) were stirred with ice-cooling and 37-40% aqueous formaldehyde (123 ml,) was added. The mixture was heated to 90-100 ° C for 16 hours and then stirred. cooled and poured into a mixture of ice (500 g) and 16N aqueous sodium hydroxide solution (250 ml), the product was extracted with ether and the extracts were washed, dried and evaporated to leave N, N-dimethyl-1- / 1- (4- chlorophenyl) cyclobutyl / -3-methylbutylamine (mp 53-55 ° C) (Formula I n = 0;

R ₁ = isobutyl; R ₂ = H; R ₃ and R ₄ = Me; R ₅ = 4-Cl and R _g = H).

Example 3

The 1- (3 ~ chloro-5-tf> ethyl) -1-cyclobutanecarbonyltril and (8.0 t) solution in ether (40 «1) added ea to the propylmagnesium nitrate solution / made by the reactions of l-branopropane (5.7 f) 1 magnesium (1.3 g) / in ether (80 ml) 1 the beaker is heated under reflux *

2.5 hours. To these 3-ethyl ether aa Iepari and then, after cooling, a solution of sodium borohydride (3.5 g) in ethanol (150 ml) was added. The mixture was maintained on ScPc 1 cup and water (50 ml) was added and then 5N hydrochloric acid (SO ml) was added.

Separate the ether layer. It was dried and evaporated so that the thick solids were crystallized from propan-2-ol so that sb gave 1 - / 1- (3-chloro-S-methyl) cyclobutyl / butylsine hydrochloride (m.p. 145-148¾).

A chlorhydrate salt made keo-kettle with ether and 5N sodium hydroxide solution and the ethereal alloy ss evaporated to give βε a suitable amine which is ee converted to N, H-ciTiethyl-1 - '/ 1- (3-chloro-5- methyl) cyclobutyl / butylethine Thiochlorhydrate (mp 14C ^g C) (Formula I n ”0 * * propyl“ H> Rg and P _{> 4} - ffei - 5 ~ C1 and Rg S-fla) by analogy ea to the one described in Example Z.

Example 4

A solution of methyl bromide (173 g) in ether (800 ml) was added to a stirred mixture of magnesium chips (45 g) in dry ether under nitrogen. The mixture was stirred without external heating for 30 minutes and then a solution of 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile (140 g) in ether (400 ml) was added under nitrogen. The mixture was refluxed for 20 hours and a solid was collected which was separated by filtration and washed and dried. the solid was mixed with ethanol (1000 ml) and sodium borohydride (70.6 g) was added in batches under a nitrogen jacket over a period of one hour. The mixture was stirred for two hours and acidified by the addition of concentrated hydrochloric acid with ice-cooling. The volume was reduced to about half by evaporation, and 12N sodium hydroxide (50 ml), water and ether were added thereto. The mixture was filtered and the ether layer was separated, washed and dried. Solvent separation gave an oil which was purified by distillation (134-138 ° C / 0.8 mm Hg) to give 1- / 1- (3,4-dichlorophenyl) cyclobutyl / ethylamine / Formula I n = 0;

R ₁ = methyl, · R ₂ , Rg and R ₄ = H? R, - = 4-C1 and R _g = 3-C1 /.

Example 5

A solution of 3,4-dichlorobenzylcyanide (25 g) and 1,3-dibromopropane (15 ml) in dry dimethyl sulfoxide (150 ml) was added dropwise under nitrogen to a stirred mixture of sodium hydride (7.5 g) which was dispersed in mineral oil (7.5 g) ) and dimethyl sulfoxide (200 ml) at a temperature in the range of 30 to 35 ° C. The mixture was stirred at room temperature for two hours and added dropwise with propan-2-ol (8 ml) and then water (110 ml).

The mixture was filtered through diatomaceous earth, which was sold under the trade name CELITE and the solid was washed with ether. The Etas layer was separated, washed with water, dried and evaporated. 1- (3,4-Dichlorophenyl) 1-cyclobutane-carbonitrile (mp 108-120 ° C at 0.15 Hg) was isolated by distillation.

A solution of 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile (70 g) in industrially methylated alcohol (200 ml) was mixed with a solution of sodium hydroxide (3.7 g) in water (5 ml) and added dropwise with a 30% solution of hydrogen peroxide. The mixture was heated to 50 ° C for one hour and then stirred with 10% palladium on charcoal (0.5 g) for one hour. The mixture was filtered and evaporated to dryness to give 1- (3,4dichlorophenyl) -1-cyclobutanecarboxamide .

The carboxamide made above was dissolved in dioxane (500 ml) and then a solution of sodium nitrite (35 g) in water (80 ml) was added dropwise. The mixture was heated to 85 to 95 ° C for 16 hours and then poured into water. The mixture was extracted with ether and the extract was back extracted with aqueous potassium carbonate. The base extract was washed with ether and acidified with concentrated hydrochloric acid to give 1- (3,4-dichlorophenyl) -1-cyclobutanecarboxylic acid (mp 120-121 ° C).

*

An acid solution (64 g) made as above in tetrahydrofuran (780 ml) was added dropwise under nitrogen to a stirred suspension of lithium aluminum hydride (9.4 g) in tetrahydrofuran (780 ml).

The mixture was refluxed for two hours and a mixture of 5% water and 95% tetrahydrofuran was added. The mixture was filtered through diatomaceous earth (CELITE - RTM) and the product extracted into ether. After washing with water and drying, the ether is evaporated to give 1- / 1- (3,4-dichlorophenyl) cyclobutyl / methylalcohol (mp 60-62 ° C).

A solution of the alcohol made as above (64 g) in pyridine (47 ml) was added dropwise to a solution of p-toluenesulfonyl chloride (54.4 g) in piricline (91 ml) which was cooled on ice. Let go ^- the temperature rises to room temperature and remains so for 18 hours. 1- / 1- (3,4-dichlorophenyl) cyclobutyl / methyl p-toluenesulfonate (m.p.

99-100 ° C) is precipitated by pouring the reaction mixture into a mixture of ice and concentrated hydrochloric acid.

*

A solution of the sulfonate compound (116.5 g) made as described above and sodium cyanide (18.2 g) in dimethylsulfoxide (400 ml) was heated in a steam bath for 18 hours. The mixture was poured into water and extracted with ether. After drying and drying, the ether is evaporated to leave a solid residue of 1- [1- (3,4-dichlorophenyl) cyclobutyl / acetonitrile].

A solution of 2- / 1- (3,4-dichlorophenyl) cyclobutyl / acetonitrile (23 g) made as described above in dry ether (50 ml) was added to a solution of ethylmagnesium bromide, which was made by adding dropwise ethyl ethyl bromide (15.83 g) in dry ether (80 ml) to a mixed mixture of magnesium chips (3.53 g) and ether (80 ml) - The mixture was refluxed for 30 minutes and stirred without further heating for 30 minutes and then refluxed for a further two hours. 1- [1- (3,4-dichlorophenyl) cyclobutyl] -2-butanyliminylmagnesium bromide was collected by filtration and a solid sample (about 1 g) was added to a solution of sodium borohydride (3 g) in diethylene glycodimethyl ether (30 ml). The mixture was stirred at 45 ° C for 90 minutes. The reaction mixture was extracted with 5N hydrochloric acid. The aqueous phase was basified with aqueous sodium hydroxide solution and extracted with ether. The ether extract is dried and the hydrogen chloride gas is introduced into the extract by depositing 1- / 1- (3,4-dichlorophenyl) cyclobutyl / methylpropylamine hydrochloride (mp 223-224 ° C) (Formula I n = 1; R4, Rj , R and R ₄ = H; R = 4-C1;

R ₆ = 3-C1; R _? = Et; R _q = H).

t

Example 6

In a similar manner to that described above (except that the reduction with sodium borohydride is carried out in methanol), 2- / 1- (4-chloro 3-trifluoromethyl) cyclobutyl / -1-methylamine chloride (mp 178-182 °) was made C) (Formula I n = 1; R ₁ , R ₂ , Rg and R ₄ = H; R $ = 4-C1; R _g = 3-CFg;

R _? = Me and R _q = H).

Example 7

A solution of 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonyl (21.1 g, made in a similar manner as described in Example 5) in ether (50 ml) was added to a solution of propyl magnesium bromide, which was made by adding a solution of propyl bromide (17.6 g ) in ether (25 ml) to a mixed mixture of magnesium chips (3.4 g) and ether (50 ml). The mixture was refluxed for 30 minutes and the ether solvent was replaced with toluene (75 ml). The reaction mixture was then heated to 105-110 ° C for one hour. After cooling to 25 ° C, a suspension of sodium borohydride (8 g) in ethanol (400 ml) was added and the mixture was refluxed for 3 hours. The mixture was cooled and water (200 ml) was added and the mixture was then acidified with 5N hydrochloric acid. Aqueous sodium hydroxide is added and the organic solvents are separated by evaporation. The residue was cooled and extracted with ether. The ether extract was washed, dried, and the hydrogen chloride gas was passed through an extract, which was then evaporated to dryness to give 1- / 1- (3,4-dichlorophenyl) cyclobutyl / butylamine chloride (mp 200-2 ° C) (Formula I n = 0; R ^ = propyl; R ₂ , R ₃ and R ₄ = H; R ₅ = 4-C1 and R _fi = 3-C1).

Example 8

An ethereal solution of isobutylmagnesium bromide is made from isobutyl bromide (16.44 g) and magnesium scrap (2.88 g) in ether (55 ml). The ether was separated by distillation and a solution was added at the same time

1- (4-Methoxyphenyl) -1-cyclobutanecarbonitrile (15 g, made in a similar manner as described in Example 1 for 1- (4-chlorophenyl) -1 cyclobutanecarbonitrile) in toluene (60 ml). The mixture was heated in a steam bath for 16 hours. After cooling, toluene (60 ml) and a suspension of sodium borohydride (4.79 g) in ethanol (125 ml) were added gently. The temperature was raised to 70 ° C during the addition and the mixture was refluxed for 90 minutes. The ethanol was then separated by evaporation.

After cooling, water (10 ml) was added dropwise and then a mixture of concentrated hydrochloric acid (32 ml) and water (32 ml) was added and the mixture was stirred for one hour. The organic phase of the mixture was washed with aqueous sodium hydroxide solution. The residue was distilled to give 1- / 1- (4-methoxyphenyl) cyclobutyl / -3-methylbutylamine (m.p.

124-127 ° C / 0.3 mm Hg) (Formula I n = 0; R ^ = isobutyl; R ₂ '^ 3 ^ 4 ⁼

H; R ₅ = 4-OMe and R _g = H).

Example 9 / 1- (4-Bromophenyl) cyclobutyl / (cyclopropyl) methylamine (m.p.

136-140 ° C / 0.1 mm Hg) was made in a similar manner as described in Example 9 except that the product was isolated from the aqueous phase of the reaction mixture (Formula I n = 0; R ^ = cyclopropyl? R ₂ , R ₃ and R ₄ =

H; R ₅ = 4-Br and Rg = H).

Example 10

An ethereal solution of butylmagnesium bromide is made from butyl bromide (6.25 g), magnesium chips (1.135 g) and ether (10 ml).

The ether was then separated by evaporation and replaced with dry toluene (20 ml) and a solution of 1- (4-chlorophenyl) -1-cyclobutanecarbonitrile (6.13 g) in dry toluene (5 ml) was added. The resulting mixture was stirred and heated in a steam bath for 18 hours after which it was cooled to room temperature and a gentle suspension of sodium borohydride (1.89 g) in absolute alcohol (50 ml) was added. During the addition, the reaction temperature rises from 30 ° to 65 ° C. When the addition is complete, the mixture is gently refluxed and held for 2.5 hours. The alcohol was then evaporated and the residue cooled while a mixture of concentrated hydrochloric acid (12.5 ml) and water (12.5 ml) was added dropwise. After stirring for 30 minutes, the toluene layer was separated and the aqueous phase was extracted with ether. The combined toluene and ether phases were washed with water and basified. The product was extracted with ether and the extracts were washed with water, dried and evaporated to give 1- (1- (4-chlorophenyl) cyclobutyl / pentylamine / Formula I n = 0? R ^ = butyl; R ₂ , R3 and R ^ =

H; R ₅ = 4-C1 and R _g = H /.

The amine prepared as above was converted to N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl / pentylamine hydrochloride (mp 182-184 ° C) by reaction with formaldehyde and formic acid in a similar manner as described in Example 2 .

Example 11

A solution of 1- (3-chloro-4-methylphenyl) -1-cyclobutanecarbonitrile (7.4 g) in dry ether (40 ml) was added dropwise to a stirred solution of propyl magnesium bromide formed by the addition of propyl bromide (6.2 g) in dry ether (10 ml) to magnesium chips (1.2 g) in dry ether (80 ml) at room temperature. The solvent is replaced with dry toluene and the mixture is heated in a steam bath for 2 hours. The solvent was evaporated to low volume in vacuo and absolute ethanol (50 ml) was added. The stirred mixture was treated with a suspension of sodium borohydride (3.22 g) in absolute ethanol (100 ml) at room temperature.

The mixture was heated to 50 ° C for 1 hour and then cooled, treated with water (30 ml) and 5N HCl (30 ml). The resulting solution was extracted with ether, washed with water, dried and evaporated to give an oil.

The oil was dried by repeated azeotropic distillation in vacuo with propan-2-ol to give 1- [1- (3-chloro-4-methylphenyl) cyclobutyl / butylamine chloride (mp above 300 ° C) / Formula I n = 0; Rf = propyl;

R, R ₃ and R ₄ = H; R ₅ = 3-C1; Rg = 4-Me / which is converted to N, N-dimethyl 1- (1- (3-chloro-4-methylphenyl) cyclobutyl / butylamine hydrochloride (mp 225-226 ° C) by reaction with formaldehyde and formic acid in a similar manner to is described in Example 2. \

Example 12

Methylmagnesium bromide was made by piercing the gases of gaseous methyl bromide through a mixed mixture of magnesium chips (0.65 g) in dry ether (15 ml). When all the magnesium was dissolved, a solution of 1- (2-naphthyl) -1-cyclobutanecarbonitrile (3.9 g) in dry ether (50 ml) was added and the mixture was refluxed for 4 hours. The progress of the reaction is monitored by thin layer chromatograph and addition. To complete the reaction, a further amount of methyl magnesium bromide made from gaseous methyl bromide, magnesium (0.65 g) in dry ether (20 ml) was added and the reaction mixture was refluxed for 3 hours. A solution of sodium borohydride (3 g) in absolute ethanol (150 ml) was added and the mixture was refluxed for 3 hours. After cooling, water and hydrochloric acid are added and the ethanol is separated by evaporation. The residue was washed with ether and basified. The resulting stock solution was extracted with ether and the extract was dried. Hydrogen chloride gas is passed through a dried extract which is evaporated to give 1- / 1- (2-naphthyl) cyclobutyl / ethylamine hydrochloride (mp 208-212 ° C) / Formula I n = 0; R1 = methyl; R2, R4 and R1 = H;

R <- and Rg together with the carbon atoms to which they are attached form a second benzene ring /.

Example 13

Isobutylmagnesium bromide is made by adding dropwise isobutyl bromide (15.34 g) in dry ether (20 ml) to a stirred mixture of magnesium chips (2.9 g) in dry ether (20 ml). 1 26 2 17 f

When all the magnesium was dissolved, a solution of 1- (4-fluorophenyl) -1-cyclobutanecarbonitrile (14.0 g) in dry ether (20 ml) was added. The ether was separated by evaporation and replaced at the same time with dry toluene (50 ml) until a temperature of 110 ° C was reached. The mixture was stirred at reflux for 2 hours, then a solution of sodium borohydride (5.0 g) in absolute ethanol (200 ml) was added and then heated at reflux for 2 hours. Cooling water (50 ml) was then added and the solution acidified with 5N HCl. The excess alcohol is separated by evaporation. The resulting solution was extracted with ether and the extract was washed and dried. Hydrogen chloride gas is passed through an extract which is evaporated to give a solid which recrystallizes from petroleum ether (i.e. 60-80 ° C) to give 1- / 1- (4-fluorophenyl) cyclobutyl / -3 -methylbutylamine chloride hydrate (mp 203-210 ° C) / Formula I n = 0; = isobutyl; R ₃ »

R ₃ and R ₄ = H; R ₅ = 4-F and R _g = H /.

Example 14

A solution of isobutyl bromide (3.16 g) in dry ether (20 ml) was added dropwise to a stirred suspension of magnesium chips (554 mg) in dry ether (20 ml) under nitrogen. Stirring was continued for 30 minutes.

The ether was then allowed to distill off and dry toluene (30 ml) was added dropwise. A solution of 1- (4-biphenyl) -1-cyclobutanecarbonitrile (5.0 g) in dry toluene (50 ml) was added dropwise over 30 minutes. After the addition was complete, the mixture was stirred and heated in a steam bath (internal temperature 90 ° C) for 68 hours. The mixture was cooled to 30 ° C and a solution of sodium borohydride (1.2 g) in absolute ethanol (60 ml) was added in batches. The resulting mixture was stirred for 1 hour without heating and then at 70 ° C for 3 hours. The mixture was cooled to 10 ° C and added dropwise with water (10 ml) and the mixture was allowed to stand overnight.

After cooling to 10 ° C, concentrated hydrochloric acid (30 ml) was added dropwise with stirring. The toluene layer was separated and the aqueous layer was extracted with ether. The combined organic layers were washed with water and dried. The dried extract was concentrated to give an orange oil which was miscible with a mixture of ether (100 ml), 40-60 ° C oetrol ether (100 ml) and 5N sodium hydroxide (100 ml) for 1 hour. The ether layer was separated and the aqueous layer was extracted with ether. The combined ether layers were washed with water and dried. Separation of the solvent gave a cream solid which distilled 174-178 ° C / 0.5 mm Hg to give a fraction which was dissolved in ether (50 ml) and added to a solution of maleic acid (1.31 g, 0.011 mol) in ether ( 100 ml). The resulting solution was cooled to give a solid which was filtered, washed with ether and dried in vacuo to

- dobivaυ yields 1- [1- (4-b'phenylyl) cyclobutyl] -3-yl] ethylbutylamine maleate (mp 135-138 ° C) / Formula 1 n = 0; = isobutyl; R ₂ , R 8 and R ₄ = H;

R ₅ = 4-phenyl; R _g = H /.

Example 15 t

A solution of isobutylmagnesium bromide is made from isobutyl bromide (12.95 g), magnesium (2.3 g) and dry ether (50 ml). Then a solution of 1- (2-naphthyl) -1-cyclobutanecarbonitrile (13.05 g) in dry toluene (30 ml) was added dropwise and the ether was distilled off simultaneously. The mixture was then stirred at 95 ° C for 18 hours, cooled to room temperature and a gentle suspension of sodium borohydride (4.0 g) in absolute ethanol (125 ml) was added. When the addition is complete, the mixture is heated to reflux for 3 hours. After standing at room temperature overnight, the ethanol was separated by evaporation and the residue was cooled to room temperature. It was added dropwise to a mixture of concentrated hydrochloric acid (50 ml) and water (50 ml) and the product was extracted with ether. The ether extracts were combined, cooled on ice and basified with 16N sodium hydroxide solution. The phases were separated and the aqueous layer was extracted with ether. The extracts were combined with a separate organic layer, washed with water, dried and evaporated to give an oil which was distilled (143-160 ° C / 0.4 mm).

Hydrogen chloride was bubbled through an oil solution (3 g) in dry ether. The solvent was removed by evaporation to give a white solid which dissolved in water. Concentrated hydrochloric acid was added. The crystalline solid upon cooling was collected and dried in vacuo at 60 ° C (2.7 g). Recrystallized from 60-80 ° C of gasoline with hot filtration to obtain 1- / 1- (2-naphthyl) cyclobutyl / -3-methylbutylamine chloride (mp 120 ° C (dec.) With a softening of 105 ° C) / Formula I n = 0; Rf = isobutyl;

R ₂ , ^R 4 and ^R 4 = H; ^R 5 and ^R 6 together with the carbon atoms to which they are attached form a second benzene ring).

Example 16

A solution of isobutylmagnesium bromide is made from isobutyl bromide (21.78 g), magnesium chips (3.9 g) and dry ether (30 ml).

The ether was distilled off and replaced at the same time with dry toluene (100 ml) until a temperature of 106 ° C was reached. Then a solution of 1- (4-bromophenyl) -1-cyclobutanecarbonitrile (25 g) in dry toluene (20 ml) was added to the hot mixture. The mixture was stirred at reflux for 1.5 hours and then cooled to room temperature. A suspension of sodium borohydride (6.6 g) in absolute ethanol (170 ml) was added gently. When the addition is complete, the mixture is left under nitrogen for 2 days and then refluxed. After refluxing for 2 hours, the mixture was cooled and added dropwise with mixtures of concentrated hydrochloric acid (50 ml) and water (50 ml) and the ethanol separated by distillation. After cooling, the layers were separated and the aqueous phase was extracted with ether. The extracts were combined with a separate toluene phase, cooled with ice water and mixed with 16N sodium hydroxide solution. The layers were separated and the aqueous phase was extracted with ether. All the organic phases were combined, washed with water, dried and evaporated to leave a yellow oil which was purified by distillation (133-139 ° C / 0.2 mm) to give a fraction which was dissolved in ether (200 ml). Dry hydrogen chloride is bubbled through the solution. The solvent was removed by evaporation in vacuo to give a white foam, which was dried by azeotropic distillation with propan-2-ol. The residue was ground with a small amount of dry ether to give a colorless solid which dissolved in hot water. The solution was evaporated to low volume and cooled on ice to give 1- / 1- (4-bromophenyl) cyclobutyl / 3-methylbutylaminchloride (mp 186-192 ° C) / Formula I n = 0; Rf = isobutyl; R ₂ , R 1 and R ₂ = H; R, - = 4-Br; Rg = H /.

Example 17

A solution of isobutyl bromide (29.45 g) in ether (30 ml) was added to a mixed mixture of magnesium (5.15 g) and ether (20 ml). After 1 hour, a solution of 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile (35.8 g) in ether (30 ml) was added. The ether was replaced with toluene (100 ml) and the resulting mixture was refluxed for two hours. Propane-2-ol (20 ml) was added and then a suspension of sodium borohydride (6 g) in propan-2-ol (125 ml) was refluxed for 3 hours. Water and then excess hydrochloric acid are added. The aqueous layer was washed with ether. The rinsing ether liquids and the organic phase of the reaction mixture are combined, dried and the solvents are separated by evaporation. The residue was collected in ether and the solution filtered. Separation of ether by evaporation afforded a residue which was extracted with petroleum ether (i.e., 40-60 ° C). Solvent separation gave a light yellow solid which dissolved in a dilute solution of sodium hydroxide. The aqueous solution was extracted with ether and the extract was mixed with the ether solution of maleic acid to give 1- (1- (3,4-dichlorophenyl) cyclobutyl / -3-methylbutyl22 amine maleate (mp 153-154%) / Formula I n = 0; R ₁ = isobutyl; R, R ₃ and R ₄ = H; R ₅ = 4-C1 and R _g = 3-term /.

- 23 -.

The Best 1 Way to Use a Finder: In an Economist Known to the Dirty

The invention can best be applied if the following procedure is used: · - · -

A solution of isobutylmagnesium bromide was made by adding under isobutylbromide nitrogen (99 g) in ether (150 ml) to a mixed mixture of magnesium chips (18 g) and ether over a period of 1.75 hours. The mixture was refluxed for 30 minutes. The ether was replaced with toluene (300 ml) and a solution of 1- (4-chlorophenyl) -1-cyclobutanecarbonitrile (97.2 g) in toluene (60 ml) was added to a solution of isobutylmagnesium bromide prepared as described above over a period of 30 minutes . The reaction mixture was heated to about 90 ° C for 19 h and then cooled.

It was added dropwise with suspensions of sodium borohydride (30 g) in ethanol (750 ml) over a period of 1.75 hours. The reaction mixture was maintained at 70 ° C for two hours and then the ethanol (580 ml) was evaporated. Water (70 ml) was added and 16 hours later concentrated hydrochloric acid (200 ml) was added dropwise. The toluene phase of the reaction mixture was washed, dried and the solvent was separated to leave a residue which was miscible with a mixture of ether and petroleum ether (i.e. 40-60 ° C) and 16N aqueous sodium hydroxide solution. The organic layer was washed, dried and evaporated to leave 1- / 1- (4-chlorophenyl) ci lobutyl / -3-methylbutylamine (mp 124-128 ° C / 0.2 mm Hg) as a brown oil (Formula I n = 0; R ^ = isobutyl; R ^, R ^ and R ^ = H; = 4-Cl and Rg = K

The primary amine (102.7 g) and 98% formic acid (310 ml) were stirred with ice-cooling and 37-40% aqueous formaldehyde (123 ml) was added. The mixture was heated to 90-100 ° C for 16 hours and then cooled and poured into a mixture of ice (500 g) and 16N aqueous sodium hydroxide solution (250 ml). The product was extracted with ether and the extracts were washed, dried and evaporated to leave N, N-dimethyl-1- / 1- (4-chlorophenyl) cyclobutyl / -3-methylbutylamine (mp 53-55 ° C) (Formula I n - 0; R ^ = isobutyl; ._ R ₂ _j = H; R ₃ and R ₄ e Me ?, R ₅ ... »4 ~ Cl_.i Rg Ji) _______

Dos: 9016/16 - DIV I

P-63/85

10. X 1989.

Claims (1)

PATENT APPLICATION / 'ΆΤΪ Srd ^: a M. copovic Go ;. ana /.i. Popovich BELGRADE - Ta ^ cska 19 Phone: 339-442 Process for the preparation of (l-arylcyclobutyl) alkylamine of the formula: CHR. (CHR ..) NR R. 1 7 nj 4 (D in which n has a value of 0 or 1; Rp when n = 0 represents a straight or branched C1-6 alkyl group, cyclopropyl or phenyl or, when n = l , R ^ represents hydrogen; Rg and are the same and represent hydrogen atoms or methyl groups; R ^ and Rg, which are the same or different, represent hydrogen, halogen, methyl, methoxy, trifluoromethyl or phenyl, or R ^ and Rg, together with the carbon atoms to which they are attached form a second benzene ring; and R 1 is methyl or ethyl; and their pharmaceutically acceptable salts, wherein the only formulas are: (V) in which. are R ^ and Rg as defined above, and Z represents a group of the formula: (a) or -CHR ₁ CR _? = NY (b) -CR = NY where are R too? as defined above and Y is the group MgX, where X is halogen, reduced with sodium hydrochloride, in a solvent such as ether, toluene, methanol, ethanol, propan-2-ol, diethylene glycoldimethyl ether or a mixture thereof, at room temperature to the reflux temperature of the reaction mixture to obtain, in the case where Z has formula (a), compounds of formula (I) in which n = 0 or, in the case where Z has formula (b), compounds of formula (I) in which is n = l, in which case Rg and hydrogen atoms are in each case; which, if necessary, is converted into a compound of formula (I) wherein R8 and R4 are methyl groups by reaction with formaldehyde and formic acid; and that the product is converted to its pharmaceutically acceptable salt as needed. THE BOOTS COMPANY PIC., Great K T hunter M.TeB4ilftP3lk442 PROCEDURE FOR OBTAINING i 1 •• arylcyclorutyl) ALKltamine -. i7T ~~~ Abstract of invention In the application, _a column for the preparation of (1-arylcyclobutyl) alkyl5 & amines! / formulas: R _{5 <z} _ ^ (Ή1? ₍ . (ΕΗ ^.) _Η ΝΗ. R, in which Rj, R $, Rg, R? in as defined in Request _y According to the process of the invention, the above compounds of formula I are prepared by reducing the compounds of formula V: where R ^ and Rg are as defined