CA1130305A

CA1130305A - Process for the preparation of n,n'-disubstituted 2-naphthaleneethanimidamide and intermediates used therein

Info

Publication number: CA1130305A
Application number: CA330,828A
Authority: CA
Inventors: Albert J. Schuster, Jr.; James R. Mccarthy
Original assignee: Dow Chemical Co
Current assignee: Dow Chemical Co
Priority date: 1978-07-03
Filing date: 1979-06-29
Publication date: 1982-08-24
Also published as: FR2430414A1; GB2024223A; GB2024223B; IT1121792B; CH641764A5; DK273079A; JPS6343382B2; JPS559095A; BE877449A; FR2430414B1; DE2926828A1; ES482113A1; NL7904774A; AR230619A1; IT7923509A0

Abstract

ABSTRACT
N,N'-disubstituted 2-naphthaleneethanimidamide is prepared by the conversion of a nitrile into the novel imido ester salt intermediate by alcoholysis followed by treatment of the intermediate with an alklamine to give the product. The final products display central nervous system activity e.g. antidepressant.

Description

The present invention is directed to a process for preparing N,N'-disubstituted 2-naphthaleneethanimidamide compounds and their pharma-ceutically-acceptable salts having the general formula (Rl) ~ CH C

(R2)m wherein R represents a loweralkyl of from 1 to 3 carbon atoms; Rl and R2 may each be located on one of the possible free positions of the naphtha-lene ring and independently represent halo, hydroxy, loweralkoxy or loweralkyl; and m and n independently represent the integers zero or one.
As used herein the terms loweralkoxy and loweralkyl refer to a moiety having from 1 to 3 carbon atoms in a chain, either branched or unbranched. The term halo refers to a halogen substitution selected from the group consist-ing of chloro, bromo, and fluoro. As used herein the term pharmaceutically-accsptable salt re~ers to an acid addition salt of the free base which is relatively innocuous to animals at dosages consis~ent with good pharmaco-dynamic activity. United States Patent 3,903,163 describes various N,N'-disubstituted 2-naphthaleneethanimidamide compounds and their pharmaceuti-cally-acceptable salts as displaying central nervous system activity.
The compounds are particularly useful as antidepressant and antianxiety agents. The active compounds were prepared by reacting 2-naphthyl-acetonitrile with a preselected primary amine and primary ammonium ion.
Alternately, the compounds vere prepared by the reaction of the corres-ponding substituted naphthylacetamide with a trialkyloxonium fluoroborate to prepare the N-alkyl substituted arylnitrilium fluoroborate salt. This was followed by the reaction of the fluoroborate salt with a primary alkylamine. Neither method of preparing the compounds was satisfactory .: - 1 -~3~305 for the production of large batches of material for commercial purposes. In carrying out the method of the present invention a compound corresponding to formula I is prepared in a two step reaction. In the first step the nitrile is converted into the corresponding imido ester salt by alcoholysis using an absolute alcohol and an anhydrous acid. In the second step the imido ester salt is treated with excess anhydrous alkylamine to give the N,N'-disubstituted napthaleneethanimidamide salt. The general reaction sequence may be re-presented as follows:
Step 1 l)n CH CN (Rl)n CH2COR3 ~ ~/ 2 ~ NH HX
~ + R30H ~ HX
~: ~ (R2)m (R2)m II III
. ~P~
:~ (Rl) ~/~ CH2CNHR
III ~ 2RNH2 ~- - ~ ~ NR-HX

~R2)m IV

wherein R, Rl, R2, n and m are as defined above, R3 is a lower alkyl generally of from one to 3 carbon atoms and X~is a halide.
The N,N'-disubstituted 2-naphthaleneethanimidamide salt ~IV) may be separated by conventional procedures such as filtering or centrifugation.
The free base may be prepared by the neutralization of the salt in an aqueous base. For example, the salt may be mixed with a molar equivalent amount of sodium hydroxide in aqueous solution, excess aqueous sodium carbonate or the like, after which the free base is separated by extraction with an organic - solvent. The salt and free base may also be further purified, if desired, ' `` ~L13~305 by using conventional procedures such as washing or recrystallization.
The present in~ention is also directed to the novel alkyl 2-naphthaleneethanimidate salts corresponding to formula III which serve as intermediates in the above reaction sequence and to a process for their preparation. Particularly preferred are compounds corresponding to formula III wherein n and m are both 0 and compounds wherein the substitutions are in the 1-, 3- or 4-position on the naphthalene moiety, of these compounds especially preferred are those bearing a chloro substitution in the 1-; position.

In the actual practice, according to step l of the above reaction a 2-naphthylacetonitrile corresponding to formula II is dissolved in a non-hydrolytic solvent, such as toluene, chloroform, or ether, and treated with ; an absolute lower alcohol such as methyl alcohol, ethyl alcohol, propyl alcohol, etc. For each equivalent of nitrile from about 1 to about 1.4 ; equivalents of alcohol are used with about 1.15 equivalents of alcohol be-ing preferred. An anhydrous pharmaceutically acceptable strong acid, generally a hydrogen halide such as hydrogen chloride or bromide, is added at such a rate that the reaction temperature does not exceed ~0C. The preferred temperature for carrying out Step 1 of the reaction is between 0 and 30C. At least one equivalent of acid is required for complete reaction and greater quantities may be added up to the saturation point without significantly affecting the reaction. The reaction is allowed ~o run until substantially all of the nitrile is converted to the imidate, generally about 15 hours. The reaction may be monitored by thin layer chromatography and the disappearance of the starting nitrile is indicative of complete reaction. The imido ester salt (III) usuall~ crystallizes from the reaction mixture and may be collected b~ filtration. The reaction should not be run above atmospheric pressure since undesirable side reactions may take place )30S

which effect the purity of the product.
Thus this invention relates to a process for the preparation of a compound of the formula:

l)n C~l2C.OR3 ~III) NH-~
~ R2)m wherein Rl and R2 are the same or different and each independently represents a halogen atom or a hydroxy group, an alkyl group of one to three carbon atoms or an alkoxy group of one to three carbon atoms; m and n are the same or dif-ferent and independently represent zero or one; R3 represents an alkyl group of one to three carbon atoms; and X represents a halogen atom; which com-prises submitting a nitrile of the formula ~ l~n~cH2cN

(II) ~R2)~

wherein Rl, R2, m and n are as previously defined, to alcoholysis using an anhydrous alkanol of one to three carbon atoms in the presence of an anhydrous hydrogen halide.
In Step 2 of the reaction sequence the imido ester salt ~III) pre-pared in Step 1 is reacted with a preselected anhydrous alkylamine in an inert solvent such as methanol, ethanol, dimethylfuran, and the like. This step may be carried out in a pressured vessel if desired. The reaction temperature is maintained at from about 45C to about 120C with from 50 to 80C being preferred. The reaction is run for a time sufficient to convert substantially all of the imido ester salt to the final product. An excess of alkylamine, '~

3~

at least two equivalents over the starting nitrile of formula II, is generally preferred to assure satisfactory yields of product.
The following examples will serve to further clarify the present invention, but are not to be construed as a limitation thereon.
Example 1: Preparation of ethyl 2-naphthaleneethanimidate hydrochloride intermediate.
The reaction vessel was charged with 40.0 grams (0.239 mol.) of 2-naphthylacetonitrile, 12.7 grams (0.274 mol.) of absolute alcohol, and 400 ml of toluene. The resulting mixture was cooled to 2C, and anhydrous hydrogen chloride was sparged in until the temperature reached 10C. A total of 17.4 grams ~0.477 mol.) of hydrogen chloride was added. After the addition was complete, the reaction mixture was stirred at 2C to 10C for about two hours.
The cooling bath was removed, and the reaction mixture allowed to warm to room temperature. The ~eaction mixture was stirred overnight during which time a white solid formed until the mixture was a thick slurry. The excess hydrogen chloride was sparged out with a stream of nitrogen. The solid was filtered off, washed with toluene, air dried, and vacuum dried to yield 57.7 grams (97% yield) of the title intermediate. The melting point was found to be 202-204C, however, the imidate salt rearranges on heating to form 2-naphthyl-acetamide.
Elemental analysis showed carbon 67.3%, hydrogen 6.70% and nitro-gen 5.62% compared to theoretical values of carbon 67.3%, hydro~en 6.46%, and nitrogen 5.61%.
Example 2: Preparation of N,N'-dimethyl 2-naphthaleneethanimidate hydrochloride In a 100 ml. reaction vessel, equipped with a stirrer, thermometer, a pressure-equalizing addition funnel, and a reflux condenser fitted with a drying tube, 11.95 grams ~0.048 mol.~ of ethyl 2-naphthaleneethanimidate 1:~303~

hydrochloride was placed~ A solution of 21.20 grams (0~683 mol.) of methyl-amine in 35 ml. of absolute ethanol was rapidly added to the reaction maxture.
The temperature quickly rose to 65C and dropped to about 30C after all of the solution was added. The reaction mixture was kept between about 50-53C
or 21 hours. The xeaction mixture was cooled to 2C and the white crystal-line product was filtered off~ The product was washed with toluene and dried to gi~e 10.2 grams (85% yield) of the title compound. The crude product was recrystallized from absolute ethanol to yield 8.97 grams of the title com-pound. The melting point was 225.5-227C
Other novel substituted imido ester salt intermediates correspond-ing to ~ormula III were also prepared using the general procedure in Example 1, These compounds are suitable or use in the process described above for the preparation of the corresponding N,N'-disubstituted 2-naphthaleneethan-imidamide. The intermediates are as follows ethyl ester l-chloro-2-naphthaleneethanimidate hydrochloride; elemental -C,H,N- calculated - 59.16, 5.32, 4,93: C~H,N - found - 57.9, 5.36, 5.08:
second analysis ~ 59.0, 5.53, 5.44 - melting at 208 degrees centigrade by di~ferential thermal analysis;
ethyl ester 6-methoxy-2-naphthaleneethanimidate hydrochloride; melts at 238-239 degrees centigrade;
ethyl ester 6-methyl-2-naphthaleneethanimidate hydrochloride; white solid, melting at 230-232 degrees C.;
ethyl ester 3-methyl-2-naphthaleneethanimidate hydrochloride; nuclear magnetic resonance-indmso-D6-delta 1.25 ppm - Triplet 3H J 7 Hert~: delta

2.5 Singlet 3H: 4~3 ppm - Singlet 2H: 4,5 ppm Quartet 2H - J equals 7 HZ delta 7~25~7,~5 - Multiplet;
ethyl ester l-h~droxy 2-naphthaleneethanimidate hydrochloride; NMR in CD30D-deuteromethanol delta 1,4-Triplet 3H J equals 7 HZ: 4.2 Singlet~ 2H: 4.5 ppm .... .

~ -6-~303~S

QuartetJ 2H J equals 7 HZ: 7~2~8~2 ~ultiplet, 6H;
ethyl ester 6-hydroxy-2-naphthaleneethanimidate hydrochloride; used directly to synthesize corresponding naphthalene ethanimidamide without further characterization~
Other intermediates correspondin~ to formula III may be prepared in a similar manner.

[ ~ ~ 6a-;-

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A method for preparing an N,N'-disubstituted 2-naphthaleneethanimid-amide or a pharmaceutically-acceptable salt thereof which comprises converting a nitrile of the formula wherein R1 and R2 may each be located on one of the possible free positions of the naphthalene ring and independently represent halo, hydroxy, lower alkyl of from one to 3 carbon atoms, or lower alkoxy of from one to 3 carbon atoms, and m and n independently represent the integers zero or one, to the corresponding imido ester salt by alcoholysis using an absolute alcohol and an anhydrous pharmaceutically-acceptable strong acid at a temperature between about 0° and 40°C; reacting the imido ester salt in an inert solvent at a temperature between about 45° to 120°C with at least two equivalents of an alkylamine having the general formula wherein R is a lower alkyl of from one to 3 carbon atoms; and recovering the pharmaceutically-acceptable salt of the N,N'-disubstituted 2-naphthalene-ethanimidamide.

2. The method of Claim 1 further including neutralizing the salt and recovering the free base.

3. The method of Claim 1 wherein the conversion of the nitrile takes place at a temperature of between about 0 and 30°C.

4. The method of claims 1 or 3 wherein the imido ester salt is reacted with the alkylamino at a temperature between about 50° and 80°C.

5. A process for the preparation of a compound of the general formula (III) wherein R1 and R2 independently represent halo, hydroxy, a lower alkyl of from one to 3 carbon atoms, or a lower alkoxy of from one to 3 carbon atoms;
m and n independently represent the integer 0 or 1; R3 represents a lower alkyl of from one to 3 carbon atoms; and X represents a halogen atom, which comprises subjecting a nitrile of the formula to alcoholysis with an absolute alcohol of the formula R3OH in the presence of an anhydrous pharmaceutically-acceptable strong acid of the formula HX.

6. The process of claim 5 wherein n and m are both 0.

7. The process of claim 5 wherein R1 is in the 1, 3 or 4 position, n is 1, and m is 0.

8. The process of claim 7 wherein R1 is 1-chloro.

9. A process for the preparation of a compound of the formula (III) wherein Rl and R2 are the same or different and each independently represents a halogen atom or a hydroxy group, an alkyl group of one to three carbon atoms or an alkoxy group of one to three carbon atoms; m and n are the same or different and independently represent zero or one; R3 represents an alkyl group of one to three carbon atoms, and X represents a halogen atom; which comprises submitting a nitrile of the formula (II) wherein R1, R2, m and n are as previously defined, to alcoholysis using an anhydrous alkanol of one to three carbon atoms in the presence of an anhydrous hydrogen halide.

10. A process according to claim 9 in which the alcoholysis is carried out at a temperature between about 0° and 40°C.

11. A process according to claim 9 in which the compound of formula (III) obtained is reacted with at least two equivalents of an alkylamine having the general formula:
R.NH2 wherein R is an alkyl group of one to three carbon atoms, and where the acid addition salt formed can be converted into the corresponding free base.

12. A process according to claim 1 in which the reaction is effected in an inert solvent at a temperature of between about 45° and 120°C.

13. A process according to claim 9 in which the starting material of formula II is 2-naphthylacetonitrile, 1-chloro-2-naphthylacetonitrile, 6-methoxy-2-naphthylacetonitrile, 6-methyl-2-naphthylacetonitrile, 3-methyl-2-naphthylacetonitrile, 1-hydroxy-2-naphthylacetonitrile or 6-hydroxy-2-naphthylacetonitrile.

14. A process according to claim 9 in which m and n are zero.

15. A process for the preparation of ethyl 2-naphthaleneethanimidate hydrochloride which comprises submitting 2-naphthylacetonitrile to alcoholysis with absolute ethyl alcohol containing excess anhydrous hydrogen chloride and recovering the ethyl 2-naphthaleneethanimidate hydrochloride so formed.

16. A compound of the formula (III) as defined in claim 9 whenever prepared by the process of claim 9 or by an obvious chemical equivalent there-of.

17. A compound of the formula (III) given in claim in which either m and n are both zero or (Rl)n is 1-chloro-, 6-methoxy-, 6-methyl-, 3-methyl, 1-hydroxy or 6-hydroxy and (R2)m is zero, whenever prepared by the process of claim 13 or by an obvious chemical equivalent thereof.

18. Ethyl 2-naphthaleneethanimidate hydrochloride whenever prepared by the process of claim 15 or by an obvious chemical equivalent thereof.

19. A process according to claim 15 in which the product is reacted with excess methylamine.