DE2926828A1 - METHOD FOR PRODUCING N, N'-DISUBSTITUTED 2-NAPHTHALINAETHANIMIDAMIDES AND THEIR SALTS AND 2-NPHTHYLIMIDOACETIC ACID ESTER SALTS - Google Patents

Description

The invention "relates to what is stated in the preceding claims featured item.

The remainders R and R _? can be the same or different. The alkyl and alkoxy radicals can be unbranched or branched. Possible halogen atoms R and R £ are fluorine, chlorine or bromine atoms. '

The preparation of salts of the compounds is preferred of the general formula I with pharmacologically acceptable acids.

In US Pat. No. 3,903,163 there are various Ν, ϊΓ-disubstituted-2-naphthalinathanimxdamxde and their salts with pharmacologically acceptable acids which have CNS activity. The compounds are particularly suitable as antidepressants and for combating anxiety. The connections are produced by reacting 2-haphthylacetonitrile with primary amines and primary ammonium ions. The connections can also be achieved by reacting the corresponding substituted naphthylacetamides with an Irialkyloxoniumfluoborat and further reacting the obtained N-alkyl-substituted Aryl nitrilium fluoroborate, with a primary alkyl amine. Neither of these procedures is for large-scale use Production of the connections satisfactory.

The invention is therefore based on the object of a new Process for the preparation of Ν, Ν'-disubstituted 2-lfaphthalinethanimidamides and to create their salts, which is technically easy to carry out and which proceeds in good yields.

In the process according to the invention, the compounds of general formula I produced in a two-step process. In the first stage the litrile becomes through alcoholysis with an anhydrous alcohol and an anhydrous acid

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converted into the corresponding imido ester salt. In the second stage, the imido ester salt obtained is used with an excess an anhydrous alkylamine to the K ^ lP-disubstituted naphthalene ethane imidamide salt implemented. The process according to the invention can be represented by the following reaction scheme will:

1st stage

CH CN.

, <Vn

+ R ₃ OH + HXrr

(H)

.CH ^ COR ₃

2nd stage

fill) + 2RNH,

CH_CNHR

² H.
NR-HX

(IV)

R, R ^, R £, m and ja have the meanings given above.

R represents an alkyl radical with generally 1 to 3 carbons

0
Substance atoms and X is a halide ion.

The UTjN'-disubstituted 2-naphthalenethanimidamide salt of general formula IV can be isolated by conventional methods, for example by filtering or centrifuging

L 909883/0826

ORIGINAL INSPECTED

yaw. The free base of the general formula I can by Neutralization of the salt made with an aqueous base will. For example, the salt with an equimolar amount of sodium hydroxide in aqueous solution or in excess aqueous sodium carbonate solution are added. The free base is then extracted with an organic solvent isolated. . The salt and free base can be further purified by conventional methods, for example by washing or recrystallization.

The invention also relates to the new 2-Naphthylimidoessig- ' acid ester salts of the general formula III, which are valuable intermediates in the process according to the invention. Particularly preferred are compounds of the general formula III in which η and m have the value 0, as well as compounds in which the substituents in the 1-, 3- or 4-position des Stand naphthalene structure. Compounds of the general formula III which are in the 1-position are particularly preferred Carry chlorine atom.

In practice, the method according to the invention is carried out as follows:

In the first stage, a 2-naphthy! Acetonitrile of the general formula II is dissolved in an inert solvent such as toluene, chloroform or an ether, and an anhydrous lower aliphatic alcohol such as methanol, ethanol or propanol is added. About 1 to 1.4 moles of alcohol are used per mole of nitrile. A quantitative ratio of 1 mol of nitrile to 1.15 mol of the alcohol is particularly preferred. A water-free, pharmacologically acceptable strong acid, generally a hydrogen halide such as hydrogen chloride or hydrogen bromide is added in such a rate that the reaction temperature not exceeding 40 ⁰ C. The preferred reaction temperature for the first stage is in the range from 0 to 30 ° C. At least 1 equivalent of the acid is required for complete conversion. Big amount of

L 909883/0826 J.

can be added up to the saturation point, but without significantly affecting the conversion. The implementation is carried out until practically all of the nitrile has been converted into the imido ester salt. This requires generally about 15 hours. The course of the reaction can be followed by thin-layer chromatography. The disappearance of the nitrile used shows the complete conversion. The imido ester salt of the general formula III usually crystallizes out of the reaction mixture and is filtered off. The implementation should not take place at higher pressures than atmospheric pressure, otherwise unwanted lifting actions take place, which affect the purity of the Affect the product.

In the second stage of the process according to the invention, the imido ester salt of the general formula III obtained is reacted with an anhydrous alkylamine in an inert solvent such as methanol, ethanol or dimethylfuran, and optionally under pressure. The reaction temperature is preferably set to a value in the range of about 4-5 to about 120 ⁰ G of from 50 to 8O ⁰ G. The reaction is carried out until practically all of the imido ester salt has been converted into the end product. In general, the alkylamine is used in excess in an amount of at least 2 equivalents per nitrile of the general formula II used, in order to achieve good yields.

The examples explain the process according to the invention.

Example i

Production of ethyl 2-naphthylimidoacetate hydrochloride

A reaction vessel is filled with 40.0 g (0.239 mol) of 2-naphthylacetonitrile, 12.7 g (0.274 mol) of anhydrous ethanol and 400 ml of toluene were charged. The resulting mixture is brought to 2 ° C cooled and then anhydrous hydrogen chloride is

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until the temperature has reached 10 ° C. A total of 17.4 g (0.477 mol) of hydrogen chloride are passed in. After the addition has ended, the reaction mixture is stirred for about 2 hours at 2 to 10 ° C. with cooling. The cooling bath is then removed and the reaction mixture is allowed to warm to room temperature. The reaction mixture is stirred for a further 15 to 18 hours. A white thick crystal slurry forms. Excess hydrogen chloride is displaced into the crystal mass by introducing nitrogen. The crystals are filtered off, washed with toluene and dried first in air and then under reduced pressure. There are obtained 57.7 g (97% of theory) of the compound from P. ^ dowel 202 to 204- ⁰ C. When heated, the imido ester salt rearranges into the corresponding 2-haphthylacetamide. Elemental analysis: CH N

found: 67.3 6.70 5.62 calc .: 67.3 6.46 5.61

B ice ρ 1 IE 2 Preparation of N, Ii ^l -Dimeth7l-2-naphthalinäthanimiaamidhydrochlorid

In a 100 ml reaction vessel, which is equipped with a stirrer, Thermometer, dropping funnel with pressure compensation and The reflux condenser is equipped with a drying tube, 11.95 g (0.048 mol) of 2 ^ naphthylimidoacetic acid ethyl ester hydrochloride submitted. Then a solution of 21.2 g (0.683 mol)

35 nil ..

Methylamine ± ψ anhydrous ethanol added quickly. The temperature of the reaction mixture rises to 65 ° C and drops to about 30 ° C once all of the solution has been added. The reaction mixture is then heated to 50 to 53 ° C. for 21 hours. The reaction mixture is then cooled to 2 ° C. and the white crystals are filtered off. The product is washed with toluene and dried. 10.2 g (85% of theory) of the title compound are obtained. The crude product is recrystallized from anhydrous ethanol. There are obtained 8.97 S of the title compound, melting at 225-227 ° C.

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According to Example 1, further new 2-naphthylimidoacetic acid ester salts are made of the general formula III produced. These compounds are suitable for the preparation of the corresponding Ν, Ν'-disubstituted 2-naphthalenethanimidamides.

The following intermediate products are produced:

ethyl l-chloro-2-naphthylimidoacetate hydrochloride; 6-methoxy-2-naphthylimidoacetic acid ethyl ester hydrochloride; 6-methyl-2-naphthylimidoacetic acid ethyl ester hydrochloride; 3-methyl-2-naphthylimidoacetic acid ethyl ester hydrochloride; Ethyl l-hydroxy-2-naphthylimidoacetate hydrochloride j o-Hydroxy - ^ - naphthylimidoacetic acid ethyl ester hydrochloride.

Other intermediates of general formula III can be prepared in a similar manner.

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Claims (9)

VOSSIUS · VOSSiUS. HILTL TAUCHNER · HEUNEMANN SIEBERTSTRASSE 4 '8OOO MUNICH 86 ■ PHONE: (O39) 474O75 CABLE: BENZOLPATENT MUNICH -TELEX 5-29 4-5 3 VO P AT D u.z .: P 226 (Vo / H) Case: D-5008 ^{3> JU} " THE DOV CHEMICAL COMPANY
Midland, Mick., V.St.A. "Process for the preparation of Ν, ΐΡ-disubstituted 2-Naphthalinäthanimidamiden and their salts and 2-naphthylimidoacetic acid ester salts " Priority: July 3, 1978, V.St.A., No. 921 690 t5: Claims (1.] Process for the preparation of !!, N'-disubstituted 2-naphthalenethanimidamides and their salts of the general formula I. in which R denotes an alkyl radical with 1 to 3 carbon atoms, R ^ and R ₂ can be bonded to free positions on the naphthalene structure and represent Halpgen atoms, hydroxyl groups, alkyl or alkoxy radicals with 1 to 3 carbon atoms and m and η have the value 0 or 1 , 909883/0826 characterized in that a 2-naphthylacetonitrile of the general formula II .CH CN (II) in which R., R ~, m and η have the above meaning, with an anhydrous alcohol and an anhydrous strong acid at temperatures from 0 to 40 ° C for reaction brings and the imido ester salt obtained in an inert solvent with at least 2 equivalents of one Alkylamine of the general formula R-NH _2j in which R is an alkyl group having 1 to 3 carbon atoms, is heated to temperatures of 4-5 ° to 120 ⁰ C. 20th 2. The method according to claim 1, characterized in that the salt obtained is neutralized and the free base isolated. 3 «A method according to claim 1, characterized in that reacting the Imidoestersalz at temperatures of 0 to 3O ⁰ C. 4-. Process according to Claim 1 or 3, characterized in that the imido ester salt is reacted with the alkylamine at temperatures of 50 to 80 ^° C. 5. The method according to claim 1 to 4-, characterized in that the 2-naphthylacetonitrile with an alcohol of the general formula R ^ -OH, in which R- is an alkyl radical with 1 to 3 carbon atoms, and a water L 909883/0826 -J free hydrogen halide of the general formula HX, in which X represents a halogen atom, to a 2-l-taphthylimidoacetic acid ester salt of the general formula III .CH ₀ COR ₀ Ί ³ .:. NH-HX in which R R-, r X, m and η are those given above Have meaning, implements. 6. 2-Naphthylimido acetic acid ester salts of the general ! Formula III BLCOR Ί ³ -. NH-HX CUi) in which R and R halogen atoms, hydroxyl groups, alkyl or alkoxy radicals having 1 to 3 carbon atoms, R, an alkyl radical having 1 to 3 carbon atoms and X represents a halogen atom and m and η denote 0 or Ί to have. 7. Compounds according to claim 6 of the general formula III, in which m and η have the O vert. 8. Compounds according to claim 6 of the general formula III, in which the radical R ^ is in the 1-, 3- or 4-position, m has the value 0 and η the value 1. 1 9. Compounds according to claim 8 of the general formula III, in which R _x . represents a chlorine atom in the 1-position. 909883/0826