United States Patent Office
Total Page：16
File Type：pdf, Size：1020Kb
2 2 4. S /3 3,385,846 United States Patent Office Patented May 28, 1968 2 The novel N-(1-cycloalken-1-yl)-azabicyclooctanes and 3,385,846 -nonanes of this invention (compounds according to For N-CYCLOALKYL-AZAfCycLooCTANES AND mula II wherein the N-cycloalkenyl group is 1-2 unsat -NONANES AND N-(2-CYCLOALKEN-1-YL)- AZABICYCLOOCTANE AND NONANE IN urated) are prepared according to known methods of con TERMEDIATES densing a cycloalkanone with a secondary amine to ob Milton E. Herr, Kalamazoo Township, Kalamazoo Coun tain the enamine product. See Stork et al., J. Am. Chem. ty, and Robert B. Moffett, Kalamazoo, Mich, assignors Soc. 85, pp. 207-222 (1963) and Blanchard, J. Org, to The Upjohn Company, Kalamazoo, Mich., a corpo Chem. 28, pp. 1397 and 1398 (1963). The particular ration of Delaware secondary amines used in the process of this invention are No Drawing. Filed Feb. 28, 1966, Ser. No. 530,323 10 2-azabicyclo[2.2.2]octane as prepared by W. Schneider 11 Claims. (CI. 260-239) and R. Dillmann, Chem. Ber. 96, 2377 (1963) and 3 azabicycio.3.2.2]-nonane as described in Belgian Patent No. 608,905 and more recently by V. L. Brown, Jr., and T. E. Stanin, Ind. Eng Chem, Prod. Res. and Dev. 4, pp. ABSTRACT OF THE DISCLOSURE 5 40-47 (1965). 2-azabicyclo[2.2.2]-octane has the for New N-cycloalkyl-azabicyclooctanes and -nonanes have mula: been prepared by condensing an azabicyclooctane or -nonane with a cycloalkanone, and reducing the thus formed enamine. The cycloalkyl group can be methyl III substituted. There are four examples describing specific 20 compounds of the invention. The compounds are central nervous system stimulants, and can be used to alleviate mental depression. The compounds form acid addition and 3-azabicyclo[3.2.2) nonane has the formula: salts and representative ones are described. Various phar maceutical forms are suggested. This invention pertains to novel organic compounds and the process for preparing the same. The invention is 30 The particular cycloalkanones used in the process of this more particularly directed to novel N-cycloalkyl-azabicy invention have the structural formula clooctanes and -nonanes, novel N-(1- or 2-cycloalken 1-yl)-azabicyclooctane and -nonane intermediates, and the novel process which comprises condensing an aza bicyclooctane or -nonane with a cycloalkanone by heat O - ( CH3)x ing in the presence of an inert organic solvent and an (CH2) acid catalyst, thus preparing an N-(1-cycloalken-1-yl)- azabicyclooctane or -nonane which is reduced, thus pre wherein m and x are as defined above. paring the corresponding N-cycloalkylazabicyclooctane or According to the stoichiometry of the reaction, one -nonane. The invention includes the novel acid addition 40 equivalent of an azobicyclooctane or -nonane is required salts of the N-cycloalkyl-azabicyclooctanes and -nonanes for each equivalent of the cycloalkanone. However, more and of the N-(2-cycloalken-1-yl)-azabicyclooctane and or less of either reactant can be used. Hence, for example, -nonane intermediates. one equivalent of 3-azabicyclo[3.2.2] nonane can be re The novel N-cycloalkyl-azabicyclooctanes and -nonanes acted with 1.5 equivalents of a cycloalkanone, e.g., cyclo of this invention have the structural formula 45 hexanone. On the other hand, one equivalent of cyclo alkanone can be reacted with 1.5 to 2 equivalents of aza CH bicyclooctane or -nonane according to the reactions de (CH3)x scribed by Stork et al., supra. Condensing a cycloalkanone and an azabicyclooctane or (CH2)n CH2)m 50 -nonane is effected by heating a mixture of the reactants in an inert organic medium, for example, benzene, tolu wherein n is an integer from 0 to 1, inclusive; m is an ene, or xylene, at temperatures ranging between about integer from 1 to 4, inclusive; and x is an integer from 75 and about 150° C., preferably between about 100 0 to 2, inclusive. and about 115 C. Advantageously, the reaction mixture The novel N-(1- or 2-cycloalken-1-yl)-azabicyclooc 5 5 should contain a strong acid catalyst which will promote tane and -nonane intermediates of this invention have the the condensation. Hydrochloric acid can be used, but structural formulas volatilizes too readily from the reaction mixture. Sulfuric acid can be used also, but sulfonic acids such as p-toluene sulfonic (most preferred), methanesulfonic, and benzene 60 sulfonic acid are preferred. The reaction mixture is ordinarily heated at the reflux O)-((4), (CH2)m temperature, using a water separator, for from about 5 to about 24 hrs. or until water separation ceases. The N-(1- and cycloalken-1-yl)-azabicyclooctane or -nonane product is recovered from the reaction mixture by fractional distilla wo (CH3)x tion under reduced pressure. The enamine product tends to y IIA be unstable, particularly in the presence of water; and, H unless used soon after preparation, it is good practice to (CH2) (C 2)m store enamines in the cold under nitrogen. 70 The novel N-(2-cycloalken-1-yl)-azabicyclooctane and wherein n, m, and x are as defined above. -nonane intermediates of this invention (compounds ac 3,385,846 3 4. cording to Formula IIA wherein the N-cycloalkenyl group solution is made basic with about 50% alkali metal hy is 2-3 unsaturated) are prepared by conventional conden droxide, e.g., sodium hydroxide and the free base N-cyclo sation of 3-halocycloalkene of the formula alkyl-azabicyclooctane or -nonane extracted with, e.g., di ethyl ether. The compound is recovered and purified by F (cH). conventional methods of washing the ether solution, dry Halogen m ing, removing the ether by evaporation, and recrystallizing w the compound from a solvent, e.g., acetone. ( CH2) The novel free base N-cycloalkyl-azabicyclooctanes and wherein m and x are as defined above, with the azabi -nonanes (Formula I) and the N-(2-cycloalken-1-yl)-aza cyclooctane or -nonane. "Halogen' can be chlorine, bro O bicyclooctanes and -nonanes (Formula IIA) of this in mine, or iodine. Illustrative 3-halocycloalkenes include vention form acid addition salts with acids. The novel acid 3-chlorocyclopentene, 3-bromocyclopentene, 3-iodocyclo addition salts of the invention are prepared by neutralizing pentene, 3 - bromocyclohexene, 3 - chlorocycloheptene, the free base compounds with an acid according to con 3-chlorocyclooctene, 3-chloro-5-methylcyclopentene, 3 ventional methods. For example, the compounds can be chloro-4,6-dimethylcyclohexene, and the like. treated with at least a stoichiometric amount of the ap The above described novel enamines (compounds ac propriate acid; and depending upon the nature of the cording to Formula II) and novel N-(2-cycloalken-1-yl)- solvent employed, the desired salt will separate spontane azabicyclooctanes and -nonanes (compounds according to ously or can be precipitated by the addition of a solvent Formula IIA) are converted into the novel N-cycloalkyl in which the salt is insoluble. Acid addition salts can also azabicyclooctanes and -nonanes of this invention (com 20 be prepared metathetically by reacting an acid addition pounds according to Formula I) by reducing the double salt of this invention with an acid which is stronger than bond of the N-cycloalken-1-yl group according to conven the acid comprising the acid moiety of the starting salt. tional methods for reducing carbon to carbon double Pharmacologically acceptable acid addition salts can be bonds. Reduction can be accomplished, for example, using prepared using acids such as sulfuric, hydrochloric, hydro hydrogen in the presence of a metal catalyst. Advanta 25 bromic, nitric, phosphoric, benzoic, p-toluenesulfonic, geously, the reduction is effected with hydrogen in the salicylic, acetic, propionic, pamoic, tartaric, citric, suc presence of a noble metal catalyst, for example platinum, cinic acids, and the like. Similarly, acid addition Salts can palladium, rhodium and the like; although base metal cata be prepared with acids such as fluosilicic acid, picric, thio lysts can be used, for example, Raney nickel, Raney co cyanic acid, and the like. balt, and the like can be used. 30 The amine-fluosilicate salts prepared by neutralizing the In general, satisfactory hydrogenations are accom free base compounds with fluosilicic acid are according to plished using the following conditions: (1) hydrogen gas U.S. Patents No. 1,915,334 and No. 2,075,359 useful as under about 15 lbs. to about 50 to 60 lbs, pressure, (2) mothproofing agents. The thiocyanate salts prepared by the catalyst (preferably platinum oxide), (3) tempera neutralizing the free base compounds with thiocyanic acid tures in the range of about 10° C. to about 100° C. (pref can be condensed with formaldehyde in accordance with erably about 25 C.), and (4) a solvent. Representative U.S. Patents No. 2,425,320 and No. 2,606,155 to form solvents include ethanol, methanol, isopropyl alcohol, gla amine thiocyanate-formaldehyde condensation products cial acetic acid, ethyl acetate, diethyl ether, dioxane, and for use as pickling inhibitors. All of the acid addition salts the like. In general, the hydrogenation proceeds readily of this invention are useful in the purification of the free and is essentially completed in about 15 mins. to about 40 bases, 2 hrs. when, for example, platinum oxide catalyst, hydro The novel N-cycloalkyl-azabicyclooctanes and -nonanes gen pressures of about 45 to 60 lbs., and a temperature of Formula I and the novel N-(1- or 2-cycloalken-1-yl)- of about 25 C. are employed. azabicyclooctane and -nonane intermediates of Formulas The N-cycloalkyl-azabicyclooctane or -nonane product II and IIA are useful organic chemicals. The latter in is recovered from the hydrogenation reaction mixture by termediates are inherently useful in accordance with the conventional methods, e.g., filtration to remove the cata invention for preparing the former.