Patented May 16, 1950 2,508,332 UNITED STATES PATENT office 2,508,332 B-PHENYL-b-PYREDYL AND 6-PHENYL-g- PPERDYLETHYL AMNES Max Hartmann and Leandro Panizzon, Riehen, Switzerland, assignors to Ciba, Pharmaceutical Products. Inc., Summit, N. J., a corporation of New Jersey No Drawing. Original application March 9, 1945, --- Serial. No. 58,971. Divided and this applica tion December 26, 1946, Serial No. 18,63. In Switzerland January 19, 1944. Section 1, Public Law 690, August 8, 1946 Patent expires January 9, 1964 13 Claims. (C. 260-293) 1 2 The present application is a division of ap For the purpose of producing the amines the plication Serial No. 581971, filed March 9, 1945. nitriles are treated with reducing agents. When According to this invention new pyridine and using a-aryl-a-pyridyl-acetonitriles, the reaction, piperidine compounds are obtained by causing by Suitable selection of the reducing agents and monoarylaceto-nitriles whose acetonitrile radical conditions, can be conducted in such a manner contains at least one hydrogen aton to re that there are formed either 3-aryl-6-pyridy act with nuclear halogenated pyridines and pi ethylamines or g-aryl-3-piperidyl-ethylamines. peridines in the presence of agents eliiniinating In this reduction of the nitriles to the amines also hydrogen halide, if desired, replacing one hydro Secondary bases are formed, besides primary gen atom at the carbon atom linked to the nitrile O bases, depending on the conditions applied. (3- group by an alkyl radical, transforming the phenyl- (3 - pyridyl - (2) - ethylamine and di- (6- nitrile group in the compounds thus obtained into phenyl-3-pyridyl- (2) -ethyl)-amine are thus ob a methyleneamino group in one or several steps, tained for example from ox-phenyl-o-pyridyl if desired, converting the resulting pyridines into (2)-acetonitrile in an alcohol solution with the corresponding piperidines by means of re 5 hydrogen in the presence of nickei catalyst at ducing agents and/or, if desired, further Sub a low temperature. The resulting primary and stituting the pyridine or piperidine compounds secondary ethylamines can be further Substituted thus obtained at the ring nitrogen aton. in the amino group according to the usual meth The monoaryl-acetonitriles used for the reac Ods. tion may contain a substituent in the methylene 20 The pyridylethylamines obtained according to group of the acetonitrile radical and one of Sev the present process can be converted into the cor eral substituents in the aryl radical. Examples responding piperidine compounds by the action are:-phenyl - acetonitrile, naphthyl - aceto of reducing agents which are known for the hy nitrile, a -phenyl-a-alkyl-acetonitriles, Such as drogenation of pyridine nucleus. a - phenyl - a - methyl-acetonitrile, 3-methoxy 25 The further Substitution at the ring nitrogen phenyl-acetonitrile, 3:4-dimethoxyphenyl-aceto atom of the pyridines and piperidines formed in nitrile, 3:4-methylene-dioxyphenyl-acetonitrile, the present process can take place in any stage Nuclear halogenated pyridines and piperidines of the reaction. The corresponding quaternary are for example:-2-chloro-pyridine, 4-chloro compounds can thus be produced for example by pyridine, 1-methyl-3-chloro-piperidine. These 30 reaction with alkyl-halides, alkyleine-halides, may also contain further substituents. Thus aryl-Sulfonic acid. eSters, dialkyl-sulfates or also 2-chloro-5-nitro-pyridine may be used as start arylalkyl-halides. It is also possible to obtain ing material. The reaction is carried out pref- - tertiary piperidines by starting. from piperidines erably in inert solvents, such as for example which are not, Substituted at the ring nitrogen ether, benzene, toluene and the like. For the 35 aton. elimination of the hydrogen halide there are The compounds produced according to the preferably used sodium, potassium, lithium as present process possess Valuable physiological such or in the form of their amides, hydrides, properties and may be used as medicaments; or alcoholates or hydrocarbon compounds, such as as intermediate products for the preparation of for example sodium amide, sodium hydride, po 40 medicanents. tassium - tertiary butylate, potassium - tertiary The following examples illustrate the inven amylate, butyl-lithium, phenyl-Sodium or phenyl tion, but are not to be regarded as liniting it lithium. in any Way:- If acetonitriles are obtained in this reaction Eacample 1 which still contain a hydrogen atom at the car 45 bon atom linked with the nitrile group, this can 80 grams of pulverized sodium amide are grad be replaced by the corresponding alkyi radicals, s ually added, while stirring and cooling, to a solu for example by reaction with alkyl halides, such tion of 117 g. of phenyl-acetonitrile and li3 g. as methyl, ethyl or diethylaminoethyl chloride of 2-chloropyridine in 400 cc. of absolute toluene. in the presence of agents eliminating hydrogen 50 The mixture is then slowly heated to 130-120 halide. C. and maintained at this temperature for it 2,508,332 3. 4. hour. Water is added thereto after cooling, the g-pyridyl-(2)-ethylamine as hydrochloride of toluene solution is shaken with dilute hydro melting point 210-211 C. and the di-B-3-meth chloric acid and the hydrochloric acid extracts oxyphenyl)-3-pyridyl-(2) -ethyll-amine as pic are made alkaline with concentrated caustic soda rate of melting point 45° C.; and from a-phenyl solution. A solid mass is separated thereby which a-pyridyl-(4)-acetonitrile the B - phenyl-3-py is taken up in ethyl acetate and distilled, or ridyl-(4) -ethylamine as hydrochloride of melt phenyl-a-pyridyl- (2)-acetonitrile passing over ing point 199 C. and the di-6-phenyl-6-py at 150-55° C. under 0.5 mm. pressure. When ridyl-(4)-ethyll-amine as picrate of melting recrystallized from ethyl acetate it melts at point 187° C. 88-89° C., the yield amounting to 135 g. 10 The formation of the primary bases can be In Similar manner there are obtained a- (3- favored by hydrogenation of the nitriles in the methoxyphenyl) - a - pyridyl-(2)-acetonitrile of presence of ammonia. For example there are melting point 54-55° C. When starting from 3 obtained: 3-phenyl-6-pyridyl-(4)-6-ethylamine methoxyphenyl-acetonitrile and 2-chloropyri of boiling point 130-135° C. under 0.2 mm. pres dine, a- (3:4-dimethoxyphenyl) - a - pyridyl-(2)- Sure, 6-naphthyl-(1)-6-pyridyl-(2)-ethylamine acetonitrile of boiling point 192-195° C. under and 3-methylene-dioxyphenyl - B - pyridyl-(2)- 0.2 mm. pressure when starting from 3:4-di ethylamine. methoxy-phenyl-acetonitrile and 2-chloropyri For example the following derivatives can be dine, a- (3:4 - methylene - dioxy - phenyl)-a-py prepared from the foregoing amines: from 6 ridyl-(2)-acetonitrile of boiling point 170-180° 20 phenyl-6-pyridyl-(2) -ethylamine by hydrogena C. under 0.5 mm. pressure When starting from tion with hydrogen in the presence of platinum 3:4-methylene-dioxyphenyl-acetonitrile and 2 catalyst the 3-phenyl-6-piperidyl - (2) - ethyl chloropyridine, a-naphthyl-(1) - a - pyridyl-(2) - amine as acetate of melting point 99 C. and acetonitrile of melting point 87° C. when start the di- IS-phenyl-6-piperidyl- (2) -ethyl)-amine ing from naphthyl-(1)-acetOnitrile and 2-chlo 23 of melting point 82° C., by condensation with ropyridine, a -phenyl-a-methyl - a - pyridyl-(2) - formaldehyde in the presence of formic acid acetonitrile of boiling point 145-150° C. under the 6-phenyl - 3 - pyridyl - (2) - ethyl-dimethyl 0.2 mm. pressure when starting from a-phenyl amine, as hydrochloride of melting point 190° C., a-methylacetonitrile and 2-chloropyridine, a by condensation with 1 mol. of formaldehyde phenyl-a-pyridyl - (4) - acetonitrile of melting 30 and hydrogenation of the resulting Schiff's base point 76-77 C, when starting from phenyl and of the pyridine nucleus with hydrogen in acetonitrile and 4-chloropyridine, a-phenyl-a- the presence of a platinum catalyst the B-phenyl ethyl-a-pyridyl- (4)-acetonitrile of boiling point (3-piperidyl-(2) -ethyl-monomethylamine of boil 193° C. under 11 mm. pressure when starting ing point 147-152 C. under, 0.1 mm. pressure, from a -phenyl-a-ethyl-acetonitrile and 4-chloro 35 by condensation with benzaldehyde and hydro pyridine, and a-phenyl-a-N-methyl-piperidyl genation at 20° C. the 3-phenyl-p-pyridyl-(2) - (3)-acetonitrile of boiling point 140-145 C. ethyl-benzylamine, by condensation with benzal under 0.2 mm. pressure when starting from dehyde and hydrogenation at 60-70° C. the B phenyl-acetonitrile and N-methyl-3-chloro phenyl - 6 - piperidyl- (2) -ethyl-benzylamine, by piperidine. 40 condensation with pyridyl- (3)-aldehyde and The indicated a-phenyl - a -alkyl - a - pyridyl hydrogenation of the Schiff's base the 6-phenyl acetonitriles can also be obtained by alkylation B - pyridyl - (2) - ethyl - pyridyl - (3) - methyll of a-phenyl-a-pyridyl-acetonitrile with the cor amine of boiling point 190-195° C. under 0.25 responding alkyl-halides in the presence of SO mm. pressure, by reaction with cyanamide the dium amide. 45 6-phenyl-3-pyridyl-(2) -ethyl-guanidine as ace Eacample 2 tate of melting point 202 C. and the corre sponding derivatives from other amines. 20 g. of the a-phenyl-a-pyridyl-(2)-acetoni Having thus disclosed the invention, what is trile described in Example 1 are dissolved in 150 claimed is: cc. of absolute ethyl alcohol and reduced at 50 1. A compound of the formula. 60-70° C. in an autoclave with hydrogen in X R presence of 5 g. of nickel catalyst. After the A-d-OH,-N, quantity of hydrogen (4 atoms) calculated for N the reduction of the -CN- group has been Pe. R s taken up, the decrease of pressure ceases. After 55 wherein Arstands for a member Selected from the suction-filtering the catalyst and evaporating group consisting of monocyclic aryl and con the solution there is obtained an oily Substance densed bicyclic aryl, X stands for a member Se from which by mixing it with 200 cc. of ethyl lected from the group consisting of hydrogen and acetate and 4 cc. of glacial acetic acid 10 g. of lower alkyl, Pestands for a member selected from the acetate of the primary base 6-phenyl-3- 60 the group consisting of pyridine and piperidine pyridyl - (2) - ethylamine can be precipitated. radicals, a carbon aton of Which is directly con The acetate melts at 124° C. and the base which nected with C, and has been liberated therefrom boils at 130 C. Ri under a pressure of 0.15 mm. The hydrochloride / melts at 210-211 C. The ethyl acetate filtrate 65 -N is evaporated, the residue is mixed with caustic Y, alkali solution and taken up in ether. The ether stands for a member selected from the group con residue consists of about 10 grams of the crude sisting of amino, lower alkylamino, lower dialkyl secondary base di-Ig - phenyl - 3 - pyridyl-(2) amino, lower aralkylamino, pyridylamino and ethyl)-amine; it melts at 84-85° C. when recrys O tallized from ether, the hydrobromide melts at 140° C. and the picrate at 179-180° C. -N^ X The following amines are prepared in analo gous manner: from a- (3-methoxyphenyl)-a-py Yoh-t-Ar ridyl-(2)-acetonitrile the 3- (3-methoxyphenyl)- fe 2,508,882 5 6 wherein Ar, X and Pe have the precedingly-re REFERENCES CATE) cited significances. The following references are of record in the 2. A primary 6-phenyl-3-pyridyl-ethylamine. file of this patent: 3. A primary (3-phenyl-6-pyridyl-(2) -ethyl FOREIGN PATENTS amine. 4. The 3-phenyl-6-pyridyl- (2) -ethylamine. liter Country Date 5. Di-I6-phenyl-6-pyridyl-ethyl)-amine. 309,300 Great Britain ------Apr. 11, 1929 6. Di-Ig-phenyl-6-pyridyl-(2)-ethyll-amine. OTHER REFERENCES 7. The di-6-phenyl - 6 - pyridyl-(2) - ethyl amine. Rupe et al., Helv. Chim. Acta 8,338-340 (1925). 8. A primary 3-phenyl-g-piperidyl-ethylamine. Journal of the American Chemical Society, vol. 9. A primary 3-phenyl-6-piperidyl-(2)-ethyi 66 (1944), pp. 725-731). amine. Chemical Abstracts 40, 31176 (1946). 10. The 6-phenyl-6-piperidyl-(2) -ethylamine. Hartman, California, and Western Medicine 66 11. Di-6-phenyl-6-piperidyl-ethyll-amine. (No. 4), 242-248 (1947). 12. Di- (3-phenyl - 6 - piperidyl - (2) - ethyl Sidgwick, Organic Chemistry of Nitrogen, page amine. 522. 13. The di-Ig-phenyl-6-piperidyl-(2) -ethyll amine. MAX HARTMANN. LEANDRO PANIZZON.