NL7904774A - PROCESS FOR PREPARING N, N'-DI-SUBSTIATED 2-Naphthalene-ethanimidamides. - Google Patents

Description

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THE DOW CHEMICAL COMPANY, Midland, Michigan, Ver. St. v. America

Process for the preparation of N, Nr-di-substituted 2-naphthalene-ethanimidamides.

The invention relates to a process for the preparation of N, N, -disubstituted 2-naphthalene ethanimidamides of the formula 1 wherein R represents an alkyl group with 1-3 carbon atoms, R 1 and R 2, which are one of the possible free sites in the naphthalene ring independently represent a halogen atom, hydroxy group, alkyl group of 1-3 carbon atoms or alkoxy group of 1-3 carbon atoms, and m and n are independently 0 or 1.

The alkyl and alkoxy groups can be straight or branched. Halogen atoms include fluorine, chlorine and bromine atoms.

The invention further relates to a process for preparing the pharmaceutically acceptable acid addition salts of the compounds of the formula 1.

US Patent 3,903,163 discloses various N, NT-di-substituted 2-naphthalene ethane imidides and their pharmaceutically acceptable salts. These compounds affect the central nervous system and are useful as antidepressants and anxiety. They are prepared by reaction of 2-naphthylacetonitrile and a primary amine and primary ammonium ion. In another method, these compounds are prepared by reacting a correspondingly substituted naphthyl acetamide and a trialkyloxonium fluoroborate followed by reaction of the formed N-alkyl substituted aryl nitrilium fluoroborate and a primary alkylamine. Neither of these methods lends itself to technical scale implementation.

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According to the invention, there is provided a process for preparing the compounds of formula 1 and their pharmaceutically acceptable salts, in two reaction steps shown in scheme A on the formula sheet. In the first step, the nitrile of the formula II is converted by alcoholysis with absolute alcohol and an anhydrous acid to the corresponding imido ester salt of the formula 3. In the second step, the imido ester salt is treated with excess anhydrous alkylamine to form the Ν, Ν'-di-substituted naphthalene ethaneimidamide salt of the formula 4. In the formulas 10 2, 3 and 4, R, R 1, R 1 and m and n have the meanings indicated above, R 1 represents an alkyl group having 1-3 carbon atoms and X is a halogen atom.

The Ν, Ν'-di-substituted 2-naphthalene ethanimidamide salt of the formula IV formed can be separated in the usual manner, such as by filtration or centrifugation. The free base can be obtained from the salt by treatment with an aqueous base. For example, the salt can be mixed with an equimolecular amount of sodium hydroxide dissolved in water or with an excess of aqueous sodium carbonate, after which the free base is separated by extraction with an organic solvent.

The salt and the free base can be further purified, if desired, by conventional methods such as washing and recrystallization.

The invention further relates to new alkyl 2-naphthalene ethane imidate salts of the formula III which are used as an intermediate in the process of the invention. For preferred compounds of formula 3, those wherein m and n are both 0, and compounds wherein the groups R 1 and R 2 are in the 1, 3, or 4 position in the naphthalene ring, particularly preferred for compounds which are in the 1-place wear a chlorine atom.

30 When executing. step 1, the 2-naphthyl acetonitrile of the formula II is dissolved in a non-hydrolyzing solvent, for example toluene, chloroform or ether, and treated with a low absolute alcohol, for example methanol, ethanol or propanol. About 1-1.4 and preferably about 1.15 equivalent alcohol is used per equivalent nitrile. An anhydrous pharmaceutically acceptable strong acid, usually a hydrogen halide, for example chlorohydrogen or hydrogen bromide, is added at a rate such that the reaction temperature does not exceed 40 ° C. Preferably step I is carried out at a temperature between 0 ° and 30 ° C. At least 1 equivalent of acid is required for a complete reaction. Larger quantities can be added up to the saturation point without adversely affecting the reaction. The conversion of the nitrile to the imidate is usually completed in about 15 hours. The progress of the reaction can be followed by thin layer chromatography, where the disappearance of the starting nitrile indicates that the reaction has been completed. The imido ester salt of the formula III formed usually crystallizes out and can be collected by filtration.

It is not recommended to carry out the reaction at higher than atmospheric pressure, because undesired side reactions may then occur, thereby adversely affecting the purity of the product.

In the second step, the imido ester salt of the formula 3 from step 1 is reacted with an appropriately selected anhydrous alkylamine in an inert solvent, for example, methanol, ethanol or dimethylfuran. If desired, this step can be performed under pressure. The reaction temperature is about 45-120 ° C and preferably 50-80 ° C. The reaction is continued until all or substantially all of the imido ester salt has been converted. Preferably, an excess of alkylamine, at least two equivalents, to the starting nitrile of formula II is used to achieve an acceptable yield.

Example I

Preparation of ethyl 2-naphthalene ethane imidate hydrochloride intermediate.

40.0 grams (0.239 mol) of 2-naphthyl acetonitrile, 12.7 grams (0.274 mol) of absolute alcohol and 400 ml of toluene were placed in a reaction vessel. After cooling the mixture to 2 ° C, anhydrous hydrogen chloride was introduced until the temperature had risen to 10 ° C. A total of 17.4 grams (0.477 mol) of hydrogen chloride were added. After this, the reaction mixture was stirred at a temperature of 2-10 ° C for about 10 hours. Afterwards, the cooling bath was removed and the temperature of the reaction mixture was allowed to rise to room temperature.

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Then the reaction mixture was stirred overnight to form a white solid until a thick slurry had formed. After removing excess hydrogen chloride with a stream of nitrogen, the solid was collected by filtration, washed with toluene, air dried and dried in vacuo. Thus, 57.7 grams (97% yield) of the title intermediate were obtained. For the melting point, a value of 202-204 ° C was found, although heating of the iimate salt causes internal rearrangement to form 2-naphthyl acetamide.

Elemental Analysis: C,% N,% Y,% 10 Calc'd: 67.3; 5.62; 6.70 found: 67.3; 5.61; 6.46

Example II

Preparation of N, N'-dimethyl 2-naphthaleneethane imidate hydrochloride.

In a 100 ml reaction vessel equipped with a stirrer, thermometer, pressure equalizing addition funnel and a reflux condenser with a drying tube, 11.95 grams (0.048 mol) of ethyl 2-naphthaleneethane imidate hydrochloride was introduced. A solution of 21.20 grams (0.683 moles) of methylamine in 35 ml of absolute ethanol was added rapidly with the temperature rapidly rising to 65 ° C and then dropping to about 30 ° C after the entire solution had been added. After this, the mixture was heated at a temperature of about 50 ° -53 ° C for 21 hours. Afterwards, the reaction mixture was cooled to 2 ° C, after which the white crystalline product formed was collected by filtration.

The product was washed with toluene and dried. Thus, 10.2 grams (85% yield) of the title compound were obtained. The crude product was recrystallized from absolute ethanol to yield 8.97 grams of the title compound, mp 225.5-227 ° C.

In the same manner as in Example I, the following new substituted imido ester salt intermediates of the formula III, suitable for the preparation of the corresponding N, N'-di-substituted 2-naphthaleneethane imidamides, were prepared: ethyl ester 1-chloro-2 -naphthalene ethanimidate hydrochloride ethyl ester 6-methoxy-2-naphthaene ethanimidate hydrochloric acid

Si 35 ethyl ester 6-methyl-2-naphthalene ethanimidate hydrochloride

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Claims (10)

A process for preparing a Ν, Ν'-disubstituted 2-naphthalene ethanimidamide or a pharmaceutically acceptable salt thereof, characterized in that a nitrile of the formula 2 wherein R 1 and R 2 each at one of the possible free sites being present in the naphthalene ring, independently representing a halogen-10 atom, hydroxy group, alkyl group with 1-3 carbon atoms or alkoxy group with 1-3 carbon atoms and m and n being independently 0 or 1, is converted into the corresponding imido salt by alcoholysis using an absolute alcohol and an anhydrous pharmaceutically acceptable strong acid at a temperature of about 15 ° -40 ° C, the imido ester salt formed is reacted with at least 2 equivalents of an alkylamine RNH wherein R represents an alkyl group having 1 to 3 carbon atoms, in an inert solvent at a temperature of about 45-120 ° C, and the pharmaceutically acceptable salt of the N, NT-di subsets formed titrated 2-naphthaleneethaneimidamide 20 is recovered. 2. Process according to claim 1, characterized in that the free base is recovered from the recovered salt by neutralization. 3. Process according to claim 1, characterized in that the conversion of the nitrile is carried out at a temperature of about 0-30 ° C. Process according to claim 1 or 3, characterized in that the reaction of the imido ester salt and the alkylamine is carried out at a temperature of about 50-80 ° C. 5. Alkyl 2-naphthaleneethane imidate salt, characterized by the formula 3 wherein R 1 and R 2 independently represent a halogen, hydroxy group, alkyl group of 1-3 carbon atoms or alkoxy group of 1-3 carbon atoms, m and n are independently 0 or 1 R 1 represents an alkyl group having 1 to 3 carbon atoms and X represents a halogen atom. /> - "v (l ^ 790 4774 i j A compound according to claim 5, characterized in that m and n in formula 3 are both 0. A compound according to claim 5, characterized in that R i is in the 1, 3 or 4 position in formula 3, 5 m is 0 and η is 1. A compound according to claim 7, characterized in that R i in formula 3 represents a chlorine atom at the I-position. 9. Pharmaceutical preparation, characterized in that the preparation as active ingredient contains a Ν, Ν'-di-substituted 2-naphthalene ethanimidamide of the formula 1 wherein R is a. alkyl group with 1-3 carbon atoms, R 1 and R 2 »each present at one of the possible free positions in the naphthalene ring, independently of each other a halogen atom, hydroxy group, alkyl group with 1-3 carbon atoms or alkoxy group with 1- 3 represent carbon atoms, 15 and m and n are independently 0 or 1, or a pharmaceutically acceptable acid addition salt thereof. Pharmaceutical preparation according to claim 9, characterized in that the active ingredient has been prepared according to the method of any one of claims 1-4. 20 0 .1 790 4774 if {ΚΛ „, * m,> VVch» -cn I 'nhr 11 reaction schedule A step 1 <R'i "Λ ΓΗΓΝ <R'n> \ / \ CHCORj 1 f ^ T ^ f RH.HX LJI J + R, 0H * HX- ^ UjKj? Ir) '(Rjirn 2 3 step 2 (R,) * - CNHR I' j * ll 3 + 2 RRHj - · - L l | \ NR.HX «V„ 4 «a ^ 7904774 ΤΗ E DOW CHEMICAL COMPAHY, of Midland, Michigan, Ver, St.v.America