CH641764A5 - IMIDOESTER SALTS AND PROCESS FOR THE SYNTHESIS OF 2-NAPHTHALENE-ETHANIMIDAMIDE N, NON-DISUBSTITUTED FROM SAID SALTS. - Google Patents

Description

The invention presented here relates to a process for the synthesis of 40 N, N'-disubstituted derivatives of 2-naphthalenethanimidamide which have the general formula:

NHR

NHR

in which R represents a lower alkyl containing between 1 and 3 carbon atoms, Rt and R2, each situated on one of the possible free positions of naphthalene, represent independently

in the form of their halogenated hydracid salts, formula in la-55 which R represents a lower alkyl containing between 1 and 3 carbon atoms, Rx and R2 can each be located on one of the possible free positions of naphthalene, and they independently represent one of the halo-, lower hydroxyalkoxyl or lower alkyl groups, and m and n independently represent the 60 whole numbers 0 or 1.

In their present use, the terms lower alkyl and lower alkoxyl refer to a fragment containing between 1 and 3 carbon atoms and which is either straight or branched. The term halo refers to a substitution with a halogen which is selected from the group consisting of chloro-, bromo- and fluoro- groups.

US Patent No. 3903163 describes many N, N'-disubstituted compounds of 2-naphthalenethanimidamide as well as their pharmaceutically acceptable salts as having a

(I)

3

641,764

activity on the central nervous system. These compounds are particularly useful as anti-anxiety and antidepressant agents. The active substances are prepared by reacting 2-naphthylacetonitrile with a selected primary amine and with a primary ammonium ion.

Alternatively, the compounds can be prepared by reacting the corresponding substituted naphthylacetamide with a trialkyloxonium fluoro-borate to synthesize the N-alkyl-substituted arylnitrilium fluoroborate salt. This is followed by the reaction of the fluoroborate salt with a primary alkylamine. Neither of the two synthesis processes has been found satisfactory when preparing large quantities of product for commercial purposes.

The invention proposes to overcome this deficiency thanks to the objects defined in the claims and more particularly the new imido ester salts of formula III, their preparation from the nitri-les of formula II and their use for the preparation of 2-naphtha -lenethanimidamides of formula I. The methods according to the invention can be represented by the following diagram:

CH_COR_ 2 II 3

NH'HX

+ HX

he

III + 2RNH,

CH-CNHR

2 II

NR * HX

where R, Ku R2, m and n are defined as above. R3 is a lower alkyl group usually containing between 1 and 3 carbon atoms and X is a halide.

The N, N'-disubstituted salt of 2-naphthalenethanimidamide can be separated by traditional methods such as filtration or centrifugation. The free base can be obtained by neutralizing the salt 40 in an aqueous medium. For example, the salt can be mixed with an equimolar amount of sodium hydroxide in aqueous solution, with an excess of aqueous sodium carbonate solution or the like, after which the free base is separated by extraction in an organic solvent. 45

The salt and the free base can still be purified, if desired, using traditional methods such as washing or recrystallization.

The compounds of formula III in which n and m are both equal to 0 are preferably taken, and the compounds in which the 50 substitutions are in positions 1-, 3- or 4- on the naphthalene ring or then those, and this preferably , which carry a chloro- substitution in position 1-.

In usual practice, in step 1 of the above scheme, a 2-naphthylacetonitrile corresponding to formula II is dissolved in a non-polar solvent such as toluene, chloroform or ether, and it is treated with an absolute lower alcohol such as methyl alcohol, ethyl alcohol, propyl alcohol, etc. Between 1 and 1.4 equivalents of alcohol are used for each equivalent of nitrile,

preferably with 1.15 equivalent. A strong anhydrous acid 60 which is acceptable from the pharmaceutical point of view is then added, generally a hydrogen halide such as hydrochloric acid or hydrobromic acid, at a rate such that the temperature does not exceed 40 ° C. The preferred temperature to carry out the step of scheme 1 is between 0 and 30 ° C. At least one equivalent of acid is required to carry out the reaction and it is possible to add larger quantities, and this up to at the saturation point without affecting the reaction for this.

The reaction is allowed to proceed until substantially all of the nitrile is converted to the imidate; it lasts about 15 hours. The progress of the reaction can be followed by analysis by thin layer chromatography and the disappearance of the stain of the original nitrile indicates the end of the reaction. The imidoester III salt usually crystallizes in the reaction medium and can be collected by filtration. The reaction should not be carried out at a pressure above atmospheric pressure since side reactions may occur, which decreases the purity of the final product.

In step 2 of the reaction sequence, the imidoester III salt prepared in step 1 reacts with a selected anhydrous alkylamine, this in an inert solvent such as methanol, ethanol, di-methylfuran and other similar solvents. This step can be carried out in a pressurized reactor if desired. The reaction temperature is maintained between about 45 and about 120 ° C, preferably with a temperature between 50 and 80 ° C. The reaction is continued for a time sufficient to convert the imidoester salt to the final product. An excess of alkylamine is generally taken, at least two more equivalents for each equivalent of the starting nitrile of formula II, so as to obtain a satisfactory yield of final product.

The following examples serve to clarify the invention presented here, but are not a limitation.

Example 1:

Preparation of ethyl 2-naphthalenethanimidate hydrochloride

The reactor is charged with 40.0 g (0.239 mol) of 2-naphthylaceto-nitrile, 12.7 g (0.274 mol) of absolute alcohol and 400 ml of toluene. The resulting mixture is cooled to 2 ° C. and then anhydrous hydrochloric acid is introduced until the temperature reaches 10 ° C. A total of 17.4 g (0.477 mol) of hydrochloric acid is added. After the completion of the addition, the mixture is stirred at 2 to 10 ° C for about 2 hours. We remove the cooling bath and

641,764

4

allow the reaction mixture to warm to room temperature. The reaction mixture is stirred overnight and it becomes a thick solution containing a white solid. The excess hydrochloric acid is removed by bubbling with a stream of nitrogen. The solid is collected by filtration, washed with toluene, allowed to air dry and then vacuum to obtain 57.7 g (yield 97%) of the title product of the example. Its melting point is obtained at 202-204 ° C; however, upon heating, the imidate salt rearranges to give 2-naphthylacetamide.

The elementary analysis indicates the following percentages: 67.3% carbon, 6.70% hydrogen and 5.62% nitrogen, which are comparable to the theoretical percentages: 67.3% carbon, 6.46% hydrogen and 5.61% nitrogen.

Example 2:

15

Preparation of N, N'-dimethyl-2-naphthalenethane-imidamide hydrochloride

11.11.95 is poured into a 100 ml reactor, equipped with an agitator, a thermometer, a pressure equalization addition funnel and a reflux condenser fitted with a dehydration tube. g (0.048 mol) ethyl 2-naphthalenethanimidate hydrochloride. A solution of 21.20 g (0.683 mol) of methylamine dissolved in 35 ml of absolute ethanol is rapidly added. The temperature rises rapidly to 65 ° C and then drops to approximately 30 ° C when all the solution has been added. The reaction mixture is kept at around 50-53 ° C for 21 h. The reaction mixture is cooled to 2 "C. and the white product which crystallizes is filtered. This product is washed with toluene and dried to obtain 10.2 g (yield 85%) of the compound described in the title of the example The crude product is recrystallized from absolute ethanol to give 8.97 g of the title compound. The melting point is 225.5-227 "C.

Other imidoester salts corresponding to formula III were prepared using the general method of Example 1. These compounds can be effectively used in the process described above for the preparation of 2-naphthalenethanimidamides N, N ' -disubsti-killed correspondents.

These imido ester salts are:

ethylester-1-chloro-2-naphthalenethanimidate hydrochloride, ethylester-6-methoxy-2-naphthalenethanimidate hydrochloride, ethylester-6-methyl-2-naphthalenethanimidate hydrochloride, ethylester-3-methyl-2- hydrochloride naphthalenethanimidate, ethyl ester-1-hydroxy-2-naphthalenethanimidate hydrochloride, ethyl ester-6-hydroxy-2-naphthalenethanimidate hydrochloride.

Other products corresponding to formula III can be prepared in a similar manner.

R

Claims (9)

641764 2 1. Compound of general formula: CH2 | jOR3 NH-HX in which R 1 and R 2 independently represent a halide, hydroxyl or lower alkyl group containing between 1 and 3 carbon atoms, or else an alkoxyl group containing between 1 and 3 carbon atoms, m and n independently represent the whole numbers 0 or 1, R3 represents a lower alkyl group containing between 1 and 3 carbon atoms, and X represents a halogen atom. 2. A compound according to claim 1, in which m and n are both 0. 3. A compound according to claim 1, in which the group Rj is located in positions 1, 3 or 4, n is 1 and m is 0. 4. The compound of claim 3, wherein Rt is 1-chloro. 5. Process for preparing the compound according to claim 1, characterized in that a nitrile of formula is subjected in which Rt and R2 are each located in one of the free positions of naphthalene and independently represent a halide, hydroxyl or lower alkyl group containing from 1 to 3 carbon atoms, or else an alkoxyl containing between 1 and 3 carbon atoms, and m and n independently represent the whole numbers 0 or 1, to an alcoholysis using an anhydrous alcohol of formula R3OH in which R3 is as defined in claim 1, in the presence of a halogenated hydracid, at a temperature situated between 0 and 40 ° C. 6. Method according to claim 5, characterized in that the alcoholysis of the nitrile takes place at a temperature between 0 and 30 ° C. 7. Process for the preparation of a halogenated hydracid salt of an N, N'-disubstituted 2-naphthalene-ethanimidamide of general formula: in one of the halo-, hydroxyl, lower alkoxyl or lower alkyl groups, X represents a halogen atom and m and n independently represent the whole numbers 0 or 1, characterized in that a salt d is reacted 'imidoester of general formula: (R,) (or) (ii) , CH COR. he NH ' HX (III) (RJ 2 m io in which R! and R2 independently represent a halide, hydroxyl, lower alkyl group containing between 1 and 3 carbon atoms, or an alkoxyl group containing between 1 and 3 carbon atoms, m and n independently represent the whole numbers 0 or 1, R3 represents a lower alkyl group containing between 1 and 3 carbon atoms, and X represents a halogen atom, with at least two equivalents of an alkylamine of general formula: R-NH2 25 2 in which R is a lower alkyl group containing between 1 and 3 carbon atoms, in an inert solvent, at a temperature between 45 and 120 ° C. 8. Method according to claim 7, characterized in that the salt is neutralized and that the free base is recovered. 9. Method according to one of claims 7 or 8, characterized in that the imidoester salt is reacted with the alkylamine at a temperature between 50 and 80 ° C.