CH637110A5 - Process for preparing novel N-(2-aminocycloheptyl)-N-alkanoyl anilides - Google Patents

Abstract

Novel N-(2-aminocycloheptyl)-N-alkanoyl anilides of the formula <IMAGE> in which the substituents are defined in Claim 1, are prepared. These compounds are obtained by reacting 1,2-cycloheptene oxide with an R-benzylamine to give a trans-2-aminocycloheptanol. This latter is then converted with sodium hydride and methanesulphonyl chloride into a corresponding mesilate. The resulting mesilate is converted into a diamine by reaction with an aniline. The benzyl group is removed from this diamine from the 2-amino nitrogen by catalytic hydrogenation, and the resulting compound is then reacted with a C3- to C6-alkenyl chloride or bromide. Finally, the acyl radical is introduced by reaction with an appropriate acid anhydride, acid chloride or acid bromide. The compounds which are obtained can be used as antidepressants.

Description

637110

PATENT CLAIM Process for the preparation of new N- (2-aminocyclo-heptyl) -N-alkanoylanilides of the formula

R

C = 0

in which mean:

R is a Cj-Cj-alkyl, C3 to Ca-cycloalkyl, vinyl, ethoxy or methoxymethyl radical;

Rj is a Cr to C3 alkyl group;

R2 C3 to C6 alkenyl;

Y and Z, which may be the same or different, represent a hydrogen atom, a halogen atom with an atomic number of 9 to 35, a trifluoromethyl radical, a Cx to C2 alkyl radical, an azido radical or a Cx to C2 alkyloxy radical, or Z in the case that Y represents a trifluoromethyl radical or azidorest, a hydrogen atom, and it applies that in the case that

that Y represents a Cj to Gj alkoxy radical and Z represents a hydrogen atom, the Cx to C2 alkyloxy radical is in the 3-position, and in the event that Y and Z both represent halogen atoms or Ca to C2 alkoxy radicals , these residues are in 3- and 4- or 3- and 5-positions,

as well as their acid addition salts,

characterized in that (a) 1,2-cycloheptenoxide with an R ^ benzylamine to form a trans-2-amino-cycloheptanol of the formula

0H-

(b) the trans-2-aminocycloheptanol with sodium hydride and then with methanesulfonyl chloride to form a mesylate of the formula

.OMs where Ms denotes -02SCH3,

(c) the reaction mixture from step (b) with a selected aniline of the formula

Y

to form a diamine of the formula

Y

H N

N

CH2

treated,

(d) the diamine from step (c) to remove the benzyl group from the 2-amino nitrogen and to form a diamine of the formula

Y

H N

Ri

2nd

5

10th

lì

20th

25th

30th

35

40

45

50

55

implements

catalytically hydrogenated,

3rd

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(e) the hydrogenated diamine from step (d) with a C3 to C8 alkenyl chloride or bromide to form an alkenylamino compound of the formula

Y

10th

N

\

Ri

15

Cs-C «

Implement alkenyl,

(f) the alkenylamino compound from step (e) with an acylating agent which is selected from the group anhydride from a carboxylic acid R-COOH and an acid chloride [R-C (0) C1]

or an acid bromide [R-C (0) Br] is selected to form the N-acylated product of the formula

25th

30th

35

Alkenyl is reacted and any compounds obtained are converted into the corresponding salts.

The invention relates to a process for the preparation of new amino-cycloaliphatic amides with pharmaceutical activity on the central nervous system. These compounds can be used as such or in the form of pharmacologically acceptable salts as drugs. It has been shown that the compounds mentioned have strong antidepressant properties which act on the central nervous system and which, after conversion into suitable pharmaceutically consumable forms of preparation and administration in suitable doses, enable them to be used as antidepressants.

By W.G. Stoll and co-workers are reported in "Helvetica Chemica Acta", volume 34, pages 1937 to 1943 (1951) about N- [2- (dimethylamino) cyclohexyl] aniline and processes for its preparation from N- (2-hydroxycyclohexyl) aniline. The authors also report that such compounds are pharmacologically active as antihistamines. However, there is no reference in the cited literature reference to the compounds according to the invention or their use as antidepressants.

J.W. Lewis and co-workers report in “The Reactions of Aromatic Nitroso-compounds with Enamines. Part I. The Reaction of Nitrosobenzene with 1-morpholine

40

45

so

-1-cyclohexene »titled article in« J. Chem. Soc. (London) (1972) », Perkins Transactions I, Part III, pages 2521 to 2524, inter alia on N- (2-morpholin-l-ylcyclo-hexyl) phenylhydroxy! Amine and its hydrochloride. However, there is no reference in the cited reference to the alkanoylanilides according to the invention or their antidepressant properties.

Furthermore, J.W. Lewis and co-workers in one with “Chemistry and Biologica! Activity of N-Substituted Hy-droxylamines »article titled in« J. Pharmaceutical Sciences », December 1974, volume 63, no. 12, pages 1951 to 1953, about some N-arylhydroxylamines, such as N- [2- (N-pyrrolodinyl) cyclohexyl] -N-phenylhydroxylamine; however, these compounds have no central nervous system properties. For example, for the alcohols, e.g. [2- (N-Piperidinyl) cyclohexyl] - (4-methoxyphenyl) methanol, a diuretic activity reported. It is also said that when the alcohol is acetylated, depressive activity occurs on the central nervous system. Furthermore, the reaction of propionyl chloride with N- [2 - (N-piperidinyl) -1, l-dimethylethyl] -N-phenylhydroxylamine to form the N-chloro compound and subsequent conversion thereof into a mixture of chlorinated aniline derivatives is reported. However, the cited literature reference lacks any reference to the compounds according to the invention, to their preparation or to their antidepressant properties.

US Pat. No. 3,510,492 discloses some 2-anilino- and 2-anilinomethylcyclo-alkylamines which are suitable as antidiabetic agents (when administered in low doses to lower the blood sugar). The structural formula IV given in column 2 of US Pat. No. 3,510,492 generally includes some of the compounds of the formula I according to the invention, but the compounds in question represent chemical intermediates on the way to their 2-anilinocycloalkylamines. In the US patent mentioned there is no indication of the practical utility of compounds of structural formula IV as end products.

The invention had for its object to provide a process for the preparation of new and promising antidepressants, namely N- (2-aminocycloheptyl) alkanoylanilides, in particular the preferred types of which should have a better therapeutic ratio or a better therapeutic index than imipramines and should also be effective over a longer period of time between administrations. The new compounds or their pharmacologically acceptable salts (optionally together with a pharmaceutical carrier) can be used in the form of a pharmaceutical dosage unit or unit dose in the treatment or control of depressive conditions in mammals and humans.

The new N- (2-aminocycloheptyi) -N-alkanoylanilides have the following formula:

55

60

65

(I)

637110

4th

in which mean:

R is a C 1-6 alkyl, C3 to C8 cycloalkyl, vinyl, ■ ethoxy or methoxymethyl radical;

Rx is a Cx to C3 alkyl group;

R2 C3 to C6 alkenyl;

Y and Z, which may be the same or different, represent a hydrogen atom, a halogen atom with an atomic number of 9 to 35, a trifluoromethyl radical, a Cr to C2 alkyl radical, an azidor radical or a Cj to C2 alkyloxy radical, or Z in the case that Y represents a trifluoromethyl radical or azidorest, a hydrogen atom, and it is true that in the event that Y represents a Cx to C2-alkyloxy radical and Z represents a hydrogen atom, the Cr to C2-alkyloxy radical is in the 3-position, and im If Y and Z both represent halogen atoms or Ct to C2 alkyloxy radicals, these radicals are in the 3- and 4- or 3- and 5-positions.

The compounds mentioned have antidepressant properties directed at the central nervous system. They can optionally be used together with a pharmaceutical carrier, in mammals or humans. The compounds in question are suitable in the form of suitable pharmaceutical dosage units or unit doses for administration to humans in doses of 4 to 400 mg per day as part of the therapy for the treatment of depressive conditions. In the case of conventional laboratory test animals which were used to determine these properties, the compounds mentioned suggest that the antidepressant properties (of the respective medicinal product) respond quickly or come to fruition. The preferred compounds also have a lower toxicity in standard laboratory tests than the usual standard antidepressant imipramine, and a longer period of activity of the test compound in the test animal. These properties enable the new compounds to be administered as antidepressants in a smaller amount and / or after a longer period between the individual administrations, for example once a day, in order to achieve a desired given antidepressant effect.

If the compounds which can be prepared according to the invention or their acid addition salts are e.g. in crystalline form as solvates, i.e. can be isolated with a very specific amount of solvent, for example water, ethanol and the like, in physical combination, the solvent can be removed per se without effective change in the chemical unit, so that solvates of this type are also intended to fall under the invention.

In formula I, the expression “C 1 -C 3 -alkyl radical” stands for a methyl, ethyl, n-propyl or isopropyl radical when defining the substituent R.

The expression “C3 to C6 cycloalkyl radical” stands for a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical. The term “C3- to Q-alkenyl radical” encompasses radicals which have non-adjacent double bonds, for example allyl, 2-butenyl and 2-methyl-2-butenyl, 2-pentenyl and 3-methyl-2-pentenyl and the various 2-hexenyl residues. “Halogen atoms with atomic numbers from 9 to 35” are fluorine, chlorine and bromine atoms.

Examples of acid addition salts of the compounds which can be prepared according to the invention, including pharmacologically acceptable salts, of compounds of the formula I are the salts of hydrogen chloride, methanesulfone, pamoe, hydrogen bromide, sulfur, vinegar, cyclohexanesulfame, p-toluoisulfone and amber -, ß-naphthalenesulfonic, maleic, fumaric, citric, lactic and oxalic acid.

For the use of the new compounds in antidepressant medicaments, the compounds in question can be in suitable pharmaceutical preparation forms, for example oral administration forms, such as tablets, powders,

Capsules and solutions or suspensions, in suitable solvents or suspending media, or parenteral administration forms, e.g. dry powders in sterile, tightly closed containers, which are mixed with a sterile solvent immediately before administration, sterile solutions or suspensions in water or other suitable solvents or suspending media, optionally together with a pharmaceutical carrier, excipient or diluent, for convenient use Ver-io delivery to patients in an amount effective for alleviating depressive conditions. As a rule, the dose of compound of the formula I or its pharmacologically acceptable salt is about 4 to about 400, preferably 50 to 200 mg. The particular is dose depends on the strength of the particular compound of formula I, the condition to be treated, the weight of the patient and other factors relevant to the decision.

The N-acylated amide compound of the formula I obtainable according to the invention can preferably be further purified by forming an acid addition salt thereof, for example the hydrochloric acid or maleic acid addition salt, and recrystallizing the amide salt from a suitable solvent or solvent mixture.

25 The inventive method for the preparation of the new compounds of formula I is characterized in that

(a) 1,2-Cycloheptenoxide

35

with a RrBenzyIamin to form a trans-2-amino-cycloheptanol of the formula

0H

50 implements

(b) the trans-2-aminocycloheptanol with sodium hydride and then with methanol sulfonyl chloride to form a mesylate of the formula

65

where Ms denotes -02SCH3,

(c) the reaction mixture from step (b) with a selected aniline of the formula

5

637110

h2n treated to form a diamine of the formula

(d) catalytically hydrogenating the diamine from step (c) to remove the benzyl group from the 2-amino nitrogen and to form a diamine of the formula

(e) the hydrogenated diamine from step (d) with a C3 to C6 alkenyl chloride or bromide to form an alkenylamino compound of the formula

Alkenvl implements,

(f) the alkenylamino compound from step (e) with an acylating agent which is selected from the group anhydride of a carboxylic acid R-COOH and an acid chloride [RC (0) C1] or an acid bromide [RC (0) Br] Formation of the N-acylated product of the formula

Alkenyl is reacted and any compounds obtained are converted into the corresponding salts.

The diamine obtained is preferably catalytically hydrogenated in the presence of a palladium-on-carbon catalyst, 20 the benzyl radical being removed in the R2 position and the trans-diamine of the formula:

25th

30th

H

KT

(VI)

35 is formed.

Preferred compounds that can be produced according to the invention are as follows:

3-chloro-4-methyl-N- [2- (N-methyl-N-allylamino) cycloheptyl] propionanilide and 40 3-trifluoromethyl-N- {2- [N-methyl-N-2-butenyl] aminocyclo -heptyl} cyclohexanecarboxanilide and the like and their acid addition salts.

If appropriate, the compounds of the formula I obtained according to the invention can be separated or dissolved in their d- and 1-optical isomers in a customary known manner. In such a case, the optical resolution or separation can take place according to at least two process variants. The separating or dissolving agents in both process variants are known, e.g. optically active Kamp-50 fersulfonic acid, bis-p-toluoyl tartaric acid, tartaric acid and di-acetyl tartaric acid. These compounds are commercially available and are usually used for the separation or dissolution of amines (bases) (cf. “Organic Syntheses”, volume V, page 932 (1973), resolution 55 or separation of R - (+) and S - (-) - a-phenylethylamine with (+) - tartaric acid).

In the first process variant for dissolving or separating the compounds mentioned, for example, one of the aminoamide compounds is converted into its optically active diastereomeric salts by reaction with a 60 optically active acid of the type mentioned in the conventional isomer separation of the type described. These diastereomeric salts can be separated from one another in a conventional manner, for example by fractional crystallization. 65 diastereomeric salts have different crystallization properties which are used in this separation. The neutralization of each diastereomeric salt with an aqueous base usually gives the ent

637110

6

speaking optically active of the free aminoamide. Each optically active free aminoamide can then be converted into the desired acid addition salt separately and in the manner described above.

In the second process variant, which is preferred for some of the compounds mentioned, the compounds of the formula I are converted into their corresponding d- and 1-isomers by first substituting the cis or trans-1,2-cycloaliphatic, asymmetrically substituted Diamine by treatment with a separating or dissolving agent, crystallization, separation and recovery of the corresponding trans-d-diamine, trans-l-diamine or the cis-d-diamine or cis-l-diamine into their corresponding d and 1 isomers transferred and then the separated diamine starting material is allowed to react with the desired carboxylic acid anhydride or halide to form the corresponding cis or trans-d- or -1-compound of formula I. The latter can then be converted into any pharmaceutically acceptable acid addition salt in the manner already described.

If the acid addition salt used to extract said new compound from its reaction mixture is not pharmacologically acceptable as such,

the corresponding free aminoamide base can be prepared from this and then converted into a pharmacologically acceptable salt in the usual known manner.

When using the new compounds as antidepressants, the compound to be used in each case from the active ingredient can be processed with a suitable pharmaceutical diluent or carrier to give a pharmaceutical preparation or a medicament for oral, parenteral or rectal administration in the form of a unit dose or unit dose. Such unit doses or dosage units are, for example, tablets, powder sachets, wafer capsules, dragees, capsules, solutions, suspensions, sterile injectable forms of administration, suppositories, bougies and the like. Suitable diluents or carriers are, for example, carbohydrates (lactose), proteins, lipids, calcium phosphate, maize starch, stearic acid, methyl cellulose and the like. These substances can be used as carriers or for the production of coatings on suitable administration forms. Water and oils, for example coconut, sesame, safflower, cottonseed or peanut oil, are suitable for the preparation of solutions or suspensions of the active ingredient. If necessary, sweeteners, colors and flavors can be added. The regulations for the dosing units or unit doses differ from new compound to new compound, they depend in particular on the physical properties of the compound mentioned or its pharmacologically acceptable salt, weight and age of the respective patient and the effect to be achieved. The pharmaceutical unit dose or dosage unit for these compounds is based on the general description given above, with about 4 to about 400 mg of compound of the formula I or their pharmacologically acceptable salt generally being contained per unit dose or dosage unit. The dosage regimen with regard to the amount of compound of the formula I should be sufficient to provide the respective patient with relief or relief from the administration of a non-toxic amount.

l to enable depression.

For oral administration, either solid or liquid dosage units or unit doses of the respective alkanoylanilide can be prepared. For the manufacture of solid forms of administration, e.g. of tablets, the compounds of formula I are mixed or blended with customary components, such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methyl cellulose and substances which function functionally similarly as pharmaceutical diluents or carriers. Wafer capsules are obtained in a similar way to tablets, the only difference being the different form and the addition of cane sugar or other sweeteners and flavors. In its simplest embodiment, capsules similar to tablets are obtained by mixing the Verbin-10 fertilizer with inert pharmaceutical diluents and filling the mixture obtained in each case into hard gelatin capsules of a suitable size. Soft gelatin capsules are obtained e.g. by mechanically encapsulating a slurry of the compound in an acceptable vegetable oil, hel-15 1's liquid petroleum jelly, or other inert oil.

Flowable unit doses or dosage units for oral administration, such as syrups, elixirs and suspensions, can also be prepared. The water-soluble forms can be dissolved in aqueous carriers together with sugar, aromati-20 flavors and preservatives to form a syrup. An elixir is usually obtained using an aqueous alcoholic (e.g. aqueous-ethanolic) vehicle and suitable sweeteners such as sugar and the sodium salt of benzoic acid sulfimide, along with aromatic flavors or adjuvants.

Suspensions are usually obtained with aqueous carriers with the addition of suspending agents such as acacia, tragacanth, methyl cellulose and the like. 30 Flowable unit doses or dosage units suitable for parenteral administration are obtained e.g. from the compounds in question and a sterile carrier, preferably water, depending on the carrier and the concentration required, the compound in question can either be suspended or dissolved in the carrier. When preparing solutions, the compounds in question are generally dissolved in water suitable for injection purposes and then sterilized by filtration before being filled into suitable vials or ampoules and sealed. Aids, e.g. Local anesthetics, preservatives and buffers, with dissolved. To improve stability, the respective mass can be frozen under vacuum after filling into the vial and removing the water. The 45 dry lyophilized powder is then usually sealed in the vial, a vial filled with water for injections being added to the vial to reprocess the liquid before use. Parenteral suspensions are obtained e.g. in practically the same manner, except that the compound is suspended therein instead of being dissolved in the carrier. In this case, too, no filtration sterilization can take place. Rather, the compound in question is sterilized by exposure to ethylene oxide before suspension in the sterile vehicle. A wetting agent or surface-active agent is expediently incorporated into the respective composition in order to better and more evenly distribute the compound.

Rectal suppositories here and below mean 60 solid bodies for insertion into the rectum, which melt or soften at body temperature and release at least one pharmacologically or therapeutically active component.

Pharmaceutically acceptable substances for the production of 65 rectal suppositories are the basis or carrier and means for increasing the melting point.

Examples of bases or carriers are cocoa butter (theobroma oil), glycerin / gelatin, carbowax, (polyoxy-

7

637110

ethylene glycol) and suitable mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the different basics can also be used. Means for increasing the melting point of suppositories are, for example, spermaceti and wax. Rectal suppositories can be prepared either by pressing or by other shaping processes. The usual weight of rectal suppositories is approximately 2.0 g.

Tablets and capsules for rectal administration are preferably obtained using the same pharmaceutically acceptable substances and according to corresponding methods as are also used or carried out in the preparation of tablets and capsules for oral administration.

Rectal suppositories, tablets or capsules can be packaged either individually in the form of unit doses or dosage units or in multiples thereof, for example in amounts of 2, 6 or 12.

The term “dosing unit” or “unit dose” refers to physically delimitable units which are suitable as dosing units or unit doses for humans and animals, each of which a given amount of active material which is aimed at achieving the desired therapeutic effect are diluents, carriers or excipients contains to understand. The regulations for such dosing units or unit doses are determined and are directly dependent on (a) the characteristics of the active material and the desired success and (b) the inherent limitations of the art of packaging an active material by administration to humans and animals.

Examples of suitable dosage units or unit doses are tablets, capsules, pills, suppositories, powder sachets, wafers, wafer capsules, teaspoons, tablespoons, drips, ampoules, vials, divided multiples of any of the administration forms mentioned and other forms of administration.

The dosage of the compound in question for treatment will depend on the route of administration and the age, weight and condition of the patient. A dosage specification of about 4 to about 400 mg, preferably from 50 to 200 mg, per day, given as a single dose or in multiple doses, corresponds to the range of effectiveness of the medicaments or pharmaceutical preparations according to the invention intended to relieve depression. The dose to be administered is calculated based on about 0.08 to about 6 mg / kg body weight of the patient. The respective compound can be brought into the form of a dosage unit with a suitable pharmaceutical carrier for convenient and effective administration. Dosage units or unit doses of medicaments preferably contain 5, 10, 25, 30, 50, 100 or 200 mg of the respective compound for systemic treatment. Sterile preparations of the active material advantageously contain 0.1 to 25% by weight of the compound in question for parenteral treatment. The dosage of at least one compound of the formula I and at least one other active ingredient-containing medicament is determined according to the actual dosage instructions for each such ingredient.

In addition to the administration of compounds of the formula I alone or as medicaments containing the main constituent, the compounds of the formula I can also be used with other active substances, e.g. Analgesics such as acetylsalicylic acid, acetaminophen, PAC compound (phenacetin / acetylsalicylic acid / caffeine), anti-inflammatory or anti-inflammatory agents such as ibuprofen and the like, anxiolytic agents such as perphenazines,

Amitriptylene hydrochloride, chlordiazepoxide, alprazolam, doxepin hydrochloride and the like can be combined.

example

TR ANS-N- [2- (ALLYLMETH YLAMINE 0) CYCL0-HEPTYL] -3 ', 4'-DICHLORPROPIONANILIDE AND HIS MALEATE SALT

Part A Trans-2- [methyl (phenyimethyl) amino] cyclo-heptanol and its fumarate salt.

A mixture of cycloheptenoxide (0.80 mol) and methyl (phenylmethyl) amine (2.4 mol) in 110 ml of water is shaken in a vibrating pressure bomb at a temperature of 125 ° C. for 24 hours. The reaction mixture is then allowed to cool to room temperature (about 30 ° C.) and saturated with about 50 g of potassium carbonate. 1 ml of a 40% aqueous sodium hydroxide solution is added and the mixture obtained is extracted 3 times with diethyl ether. The ether layers are combined, dried with anhydrous magnesium sulfate and then concentrated by evaporating the ether. Distillation of the crude product gives the alcohol mentioned in the title, which is converted into the fumarate salt.

Part B Trans-3,4-dichloro-N- {2- [methyl (phenylmethyl) amino] cyclohepty 1} aniline and its oxalate.

A mixture of trans-2- [methyl (phenylmethyl) amino] cycloheptanol (0.10 mol) and 0.10 mol sodium hydride (50% dispersion in oil) in 50 ml tetrahydrofuran (THF) is on the steam bath for 1 hour heated for a long time and then cooled with ice. 0.10 moles of methanesulfonyl chloride in 25 ml of THF are added to the mixture over 30 minutes to give the methanesulfonyl ester. Then 3,4-dichloroaniline (0.20 mol) are added in one portion. The THF solvent is removed by distillation and the mixture is heated on a steam bath for about 16 hours. Then 200 ml of 20% aqueous sodium hydroxide are added and the mixture is heated for a further 1 hour. The reaction mixture is extracted with 10% aqueous hydrochloric acid. The acidic layer is washed with diethyl ether, made basic with 40% aqueous NaOH and extracted with 150 ml of diethyl ether. The ether layer is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and the ether is removed by evaporation. Distillation of the crude product gives the diamine mentioned in the title. The compound obtained is converted into the oxalate salt.

Part C Trans-3,4-dichloro-N- [2- (methylamino) cycloheptyl] aniline

A mixture of trans-3,4-dichloro-N- [2- [methyl (phenylmethyl) aminocycloheptyl] aniline (0.1 mol) and 10% palladium-on-carbon in ethyl acetate or ethanol is added to a hydrogen pressure of 3.52 kg / cm2 hydrogenated in a pair device. The mixture is then filtered to remove the catalyst and the solvent is removed by evaporation. The diamine mentioned in the title can be further purified by converting it into an acid addition salt.

Part D Trans-3,4-dichloro-N- [2- (allylmethylamino) cyclo-heptyl] aniline

A mixture of trans-3,4-dichloro-N- [2- (methylamino) cycloheptyl] aniline (8.0 mol), potassium carbonate (1.1 g) and allyl bromide (8.0 mol) in 10 ml of dimethylformamide and 40 ml of benzene is heated at the reflux for 16 hours.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

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The mixture is then allowed to cool, washed with water and saturated saline and concentrated to remove the solvent. The diamine mentioned in the title is further purified by column chromatography or by conversion into an acid addition salt with subsequent recrystallization.

Part E Method 1 Trans-N - [- allylmethylamino) cyclo-

heptyl] -3 ', 4'-dichloropropionanilide and its maleate salt A solution of trans-3,4-dichloro-N- [2- (allylmethylamino) cycloheptyl] aniline (10.0 mmol) in 10 ml propionic acid anhydride heated on the steam bath overnight. Then 100 ml of water are added and the mixture is heated for a further hour in order to decompose the excess of the anhydride. By adding 25 ml of 20% aqueous NaOH, the solution is made basic and extracted with diethyl ether. The ether extract is washed with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated to remove the solvent. The crude amide mentioned in the title is obtained by

8th

Conversion into the maleate salt and subsequent recrystallization is cleaned.

Part E Method 2 Trans-N- [2- (allylmethylamino) cyclo-s heptyI] -3'4'-dichloropropionanilide and its maleate salt An ice-cooled solution of trans-3,4-dichloro-N - [2- ( allylmethylamino) -cycloheptyl] aniline (0.010 mol) and triethylamine (0.020 mol) in 100 ml of diethyl ether, 0.020 mol of propionyl chloride is added in 30 minutes. The reaction mixture obtained is stirred for 16 hours at room temperature (about 20 ° C.) and then 100 ml of saturated aqueous sodium bicarbonate solution are added. The organic layer is separated, washed with water and then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to give the propionanilide mentioned in the title. This oil is dissolved in a mixture of 10 ml of methanol and 75 ml of diethyl ether, and 0.010 mol of maleic acid is added, 20 which forms the maleic acid salt of the propionanilide mentioned in the title.

v